The impact of early oral anticancer medication monitoring through electronic patient assessments

Authors

Josh DeClercq

Department of Biostatistics

Vanderbilt University Medical Center

Published

December 5, 2024

1 Study Overview

1.1 Background

Specialty pharmacists can play a role in managing the growing number of oral anticancer medications as preferred cancer treatments.

Adverse effects may occur early in oral chemotherapy, limiting a patient’s ability to stay on the therapy. Electronic health record patient portals are an easy way to communicate to patients and can be utilized as a tool for reporting adverse effects.

The purpose of this study is to evaluate the effectiveness and feasibility of using an automated patient assessment communicated within the electronic health portal at identifying early adverse effects that require pharmacist intervention. This will be the first study to evaluate the effect of using technology to support patient monitoring on patient outcomes.

1.2 Methods

This is a prospective randomized study evaluating adult oncology patients prescribed new oral anticancer medication from providers associated with Vanderbilt Ingram Cancer Center and filled at VSP from 09/01/23 to 01/31/24.

Control: Usual care (Patients get follow up phone call 5-7 days before the time of their refill is due).

Intervention: Automated patient assessment sent 7-14 days after initial dispense of a new oral anticancer cancer medication

1.3 Outcomes

Aim 1: To evaluate differences in timing and frequency of adverse effect (AE) identification resulting in a pharmacist intervention during the first 45 days of treatment between intervention and usual care (control).
Aim 2: To evaluate the difference in medication changes and clinical outcomes at 90 days after initial medication dispense between intervention and usual care (control).

1.4 Exclusions

Exclude if patient never start treatment or discontinue within 14 days of initiation

Exclude if patient is prescribed a specialty medication for a hematologic condition

2 Descriptive statistics

2.1 Patient information

Characteristic	N	Study assignment		Overall, N = 387¹
Characteristic	N	Case, N = 182¹	Control, N = 205¹	Overall, N = 387¹
Age group	387
< 60		59 (32.4%)	61 (29.8%)	120 (31.0%)
>= 60		123 (67.6%)	144 (70.2%)	267 (69.0%)
Sex	387
Female		71 (39.0%)	89 (43.4%)	160 (41.3%)
Male		111 (61.0%)	116 (56.6%)	227 (58.7%)
Patient race	86
White		30 (85.7%)	41 (80.4%)	71 (82.6%)
Black		2 (5.71%)	4 (7.84%)	6 (6.98%)
Asian		0 (0%)	3 (5.88%)	3 (3.49%)
Hispanic/Latino/a		1 (2.86%)	0 (0%)	1 (1.16%)
Middle Eastern or North African		0 (0%)	1 (1.96%)	1 (1.16%)
None of these		1 (2.86%)	1 (1.96%)	2 (2.33%)
Prefer Not to Answer		0 (0%)	1 (1.96%)	1 (1.16%)
Unable to provide		1 (2.86%)	0 (0%)	1 (1.16%)
Missing		147	154	301
Patient ethnic group	86
Mexican, Mexican American, or Chicano/a		1 (2.86%)	0 (0%)	1 (1.16%)
Other Hispanic, Latino/a, or Spanish origin		1 (2.86%)	0 (0%)	1 (1.16%)
None of these		27 (77.1%)	44 (86.3%)	71 (82.6%)
Prefer Not to Answer		4 (11.4%)	2 (3.92%)	6 (6.98%)
Unable to Provide		2 (5.71%)	5 (9.80%)	7 (8.14%)
Missing		147	154	301
¹ n (%)

2.2 Disease information

Characteristic	N	Study assignment		Overall, N = 387¹
Characteristic	N	Case, N = 182¹	Control, N = 205¹	Overall, N = 387¹
Diagnosis	387
Bladder		0 (0%)	1 (0.49%)	1 (0.26%)
Bone		0 (0%)	1 (0.49%)	1 (0.26%)
Breast		32 (17.6%)	30 (14.6%)	62 (16.0%)
Central nervous system		24 (13.2%)	20 (9.76%)	44 (11.4%)
colon		4 (2.20%)	15 (7.32%)	19 (4.91%)
gastric		2 (1.10%)	3 (1.46%)	5 (1.29%)
head and neck		1 (0.55%)	0 (0%)	1 (0.26%)
hepatobiliary		2 (1.10%)	8 (3.90%)	10 (2.58%)
kidney		15 (8.24%)	21 (10.2%)	36 (9.30%)
lung (non-small cell, small cell)		7 (3.85%)	12 (5.85%)	19 (4.91%)
Melanoma (skin)		8 (4.40%)	3 (1.46%)	11 (2.84%)
Neuroendocrine and adrenal		0 (0%)	1 (0.49%)	1 (0.26%)
Pancreatic adenocarcinoma		4 (2.20%)	5 (2.44%)	9 (2.33%)
Prostate		68 (37.4%)	59 (28.8%)	127 (32.8%)
rectal		6 (3.30%)	8 (3.90%)	14 (3.62%)
soft tissue sarcoma		6 (3.30%)	8 (3.90%)	14 (3.62%)
thyroid		1 (0.55%)	7 (3.41%)	8 (2.07%)
uterine		2 (1.10%)	3 (1.46%)	5 (1.29%)
Diagnosis category	387
Breast		32 (17.6%)	30 (14.6%)	62 (16.0%)
Central nervous system		24 (13.2%)	20 (9.76%)	44 (11.4%)
GI		18 (9.89%)	40 (19.5%)	58 (15.0%)
GU		83 (45.6%)	81 (39.5%)	164 (42.4%)
GYN		2 (1.10%)	3 (1.46%)	5 (1.29%)
Head/neck		2 (1.10%)	7 (3.41%)	9 (2.33%)
Lung		7 (3.85%)	12 (5.85%)	19 (4.91%)
Melanoma/sarcoma		14 (7.69%)	12 (5.85%)	26 (6.72%)
What is the patient's cancer stage?	387
stage I		8 (4.40%)	9 (4.39%)	17 (4.39%)
stage II		28 (15.4%)	21 (10.2%)	49 (12.7%)
stage III		36 (19.8%)	30 (14.6%)	66 (17.1%)
stage IV		107 (58.8%)	142 (69.3%)	249 (64.3%)
staging not available		3 (1.65%)	3 (1.46%)	6 (1.55%)
¹ n (%)

2.3 Medication

Characteristic	N	Study assignment		Overall, N = 387¹
Characteristic	N	Case, N = 182¹	Control, N = 205¹	Overall, N = 387¹
Drug class category	387
Anti-neoplastic agents		112 (61.5%)	146 (71.2%)	258 (66.7%)
Anti-androgens/hormone receptor antagonists		70 (38.5%)	59 (28.8%)	129 (33.3%)
Medication name (Epic prescription)	387
relugolix		42 (23.1%)	38 (18.5%)	80 (20.7%)
capecitabine		20 (11.0%)	32 (15.6%)	52 (13.4%)
temozolomide		21 (11.5%)	14 (6.83%)	35 (9.04%)
abiraterone acetate		7 (3.85%)	11 (5.37%)	18 (4.65%)
abemaciclib		11 (6.04%)	5 (2.44%)	16 (4.13%)
lenvatinib mesylate		3 (1.65%)	11 (5.37%)	14 (3.62%)
cabozantinib s-malate		7 (3.85%)	6 (2.93%)	13 (3.36%)
ribociclib succinate		5 (2.75%)	7 (3.41%)	12 (3.10%)
axitinib		4 (2.20%)	6 (2.93%)	10 (2.58%)
lomustine		6 (3.30%)	4 (1.95%)	10 (2.58%)
enzalutamide		5 (2.75%)	4 (1.95%)	9 (2.33%)
palbociclib		3 (1.65%)	6 (2.93%)	9 (2.33%)
belzutifan		1 (0.55%)	7 (3.41%)	8 (2.07%)
darolutamide		5 (2.75%)	3 (1.46%)	8 (2.07%)
osimertinib mesylate		0 (0%)	7 (3.41%)	7 (1.81%)
pazopanib hcl		3 (1.65%)	4 (1.95%)	7 (1.81%)
apalutamide		5 (2.75%)	1 (0.49%)	6 (1.55%)
dabrafenib mesylate		2 (1.10%)	3 (1.46%)	5 (1.29%)
abiraterone		4 (2.20%)	0 (0%)	4 (1.03%)
ivosidenib		1 (0.55%)	3 (1.46%)	4 (1.03%)
tivozanib hcl		2 (1.10%)	2 (0.98%)	4 (1.03%)
trifluridine/tipiracil hcl		1 (0.55%)	3 (1.46%)	4 (1.03%)
adagrasib		2 (1.10%)	1 (0.49%)	3 (0.78%)
brigatinib		3 (1.65%)	0 (0%)	3 (0.78%)
elacestrant hcl		2 (1.10%)	1 (0.49%)	3 (0.78%)
encorafenib		0 (0%)	3 (1.46%)	3 (0.78%)
everolimus		0 (0%)	3 (1.46%)	3 (0.78%)
fruquintinib		0 (0%)	3 (1.46%)	3 (0.78%)
imatinib mesylate		1 (0.55%)	2 (0.98%)	3 (0.78%)
nirogacestat hydrobromide		2 (1.10%)	1 (0.49%)	3 (0.78%)
ribociclib		1 (0.55%)	2 (0.98%)	3 (0.78%)
binimetinib		2 (1.10%)	0 (0%)	2 (0.52%)
capmatinib hydrochloride		0 (0%)	2 (0.98%)	2 (0.52%)
larotrectinib sulfate		1 (0.55%)	1 (0.49%)	2 (0.52%)
tepotinib hcl		1 (0.55%)	1 (0.49%)	2 (0.52%)
trifluridine/tipiracil		2 (1.10%)	0 (0%)	2 (0.52%)
tucatinib		1 (0.55%)	1 (0.49%)	2 (0.52%)
alpelisib		0 (0%)	1 (0.49%)	1 (0.26%)
capivasertib		1 (0.55%)	0 (0%)	1 (0.26%)
dabrafenib mesylate, trametinib		0 (0%)	1 (0.49%)	1 (0.26%)
darolutamide; relugolix		0 (0%)	1 (0.49%)	1 (0.26%)
entrectinib		0 (0%)	1 (0.49%)	1 (0.26%)
everolimus + lenvima		1 (0.55%)	0 (0%)	1 (0.26%)
futibatinib		0 (0%)	1 (0.49%)	1 (0.26%)
lenvatinib		0 (0%)	1 (0.49%)	1 (0.26%)
lorlatinib		1 (0.55%)	0 (0%)	1 (0.26%)
osimertinib		0 (0%)	1 (0.49%)	1 (0.26%)
ripretinib		1 (0.55%)	0 (0%)	1 (0.26%)
selinexor		1 (0.55%)	0 (0%)	1 (0.26%)
selpercatanib		1 (0.55%)	0 (0%)	1 (0.26%)
¹ n (%)

2.4 ECOG and health status

ECOG describes the patients’ level of functioning in terms of their ability to care for themselves. This score is assigned by the healthcare provider. Score of 0 is fully active while score of 5 is dead.

Characteristic	N	Study assignment		Overall, N = 387¹
Characteristic	N	Case, N = 182¹	Control, N = 205¹	Overall, N = 387¹
What line of treatment is this medication?	385
1st line		72 (39.8%)	98 (48.0%)	170 (44.2%)
2nd line		51 (28.2%)	52 (25.5%)	103 (26.8%)
3rd line		27 (14.9%)	27 (13.2%)	54 (14.0%)
4th line or higher		31 (17.1%)	27 (13.2%)	58 (15.1%)
Missing		1	1	2
What was the ECOG score before the the prescription was sent out?	387
0		65 (35.7%)	69 (33.7%)	134 (34.6%)
1		79 (43.4%)	93 (45.4%)	172 (44.4%)
2		12 (6.59%)	20 (9.76%)	32 (8.27%)
3		0 (0%)	2 (0.98%)	2 (0.52%)
Unknown or not documented		26 (14.3%)	21 (10.2%)	47 (12.1%)
Charlson Comorbidity Index Score	387
Mean (SD)		6.8 (2.8)	7.3 (2.7)	7.1 (2.7)
Median (IQR)		7.0 (5.0 - 9.0)	8.0 (5.0 - 9.0)	7.0 (5.0 - 9.0)
Range		2.0 - 16.0	0.0 - 14.0	0.0 - 16.0
¹ n (%)

Characteristic	N	Study assignment		Overall, N = 387¹
Characteristic	N	Case, N = 182¹	Control, N = 205¹	Overall, N = 387¹
Myocardial infarction	387	9 (4.95%)	6 (2.93%)	15 (3.88%)
Congestive heart failure	387	7 (3.85%)	8 (3.90%)	15 (3.88%)
Peripheral vascular disease	387	17 (9.34%)	14 (6.83%)	31 (8.01%)
Cerebrovascular accident (CVA) or transient ischemic attack (TIA)	387	6 (3.30%)	8 (3.90%)	14 (3.62%)
Dementia	387	0 (0%)	1 (0.49%)	1 (0.26%)
COPD	387	5 (2.75%)	8 (3.90%)	13 (3.36%)
Connective tissue disease	387	11 (6.04%)	14 (6.83%)	25 (6.46%)
Peptic ulcer disease	387	0 (0%)	6 (2.93%)	6 (1.55%)
Liver disease	387
None		176 (96.7%)	197 (96.1%)	373 (96.4%)
Mild		3 (1.65%)	3 (1.46%)	6 (1.55%)
Moderate to severe		3 (1.65%)	5 (2.44%)	8 (2.07%)
Diabetes mellitus	387
None or diet-controlled		156 (85.7%)	173 (84.4%)	329 (85.0%)
Uncomplicated		26 (14.3%)	32 (15.6%)	58 (15.0%)
Hemiplegia	387	0 (0%)	2 (0.98%)	2 (0.52%)
Moderate to severe CKD	387	16 (8.79%)	20 (9.76%)	36 (9.30%)
Solid tumor	387
None		0 (0%)	2 (0.98%)	2 (0.52%)
Localized		85 (46.7%)	64 (31.2%)	149 (38.5%)
Metastatic		97 (53.3%)	139 (67.8%)	236 (61.0%)
Leukemia	387	1 (0.55%)	2 (0.98%)	3 (0.78%)
Lymphoma	387	3 (1.65%)	2 (0.98%)	5 (1.29%)
AIDS	387	1 (0.55%)	2 (0.98%)	3 (0.78%)
¹ n (%)

2.5 Questionnaire response

Characteristic	N	Study assignment		Overall, N = 387¹
Characteristic	N	Case, N = 182¹	Control, N = 205¹	Overall, N = 387¹
Questionnaire response	387
Yes		85 (46.7%)	0 (0%)	85 (22.0%)
No		97 (53.3%)	205 (100.0%)	302 (78.0%)
Have you started taking your medication?	85
No		3 (3.53%)	0 (NA%)	3 (3.53%)
Yes		82 (96.5%)	0 (NA%)	82 (96.5%)
Missing		97	205	302
How many doses have you missed since your first dose	85
0		79 (92.9%)	0 (NA%)	79 (92.9%)
1 to 2		3 (3.53%)	0 (NA%)	3 (3.53%)
3 or more		3 (3.53%)	0 (NA%)	3 (3.53%)
Missing		97	205	302
New side efects since new medication start?	82
No		55 (67.1%)	0 (NA%)	55 (67.1%)
Yes		27 (32.9%)	0 (NA%)	27 (32.9%)
Missing		100	205	305
How bad are the side effects?	27
not bad		12 (44.4%)	0 (NA%)	12 (44.4%)
I can tolerate them		14 (51.9%)	0 (NA%)	14 (51.9%)
really bad		1 (3.70%)	0 (NA%)	1 (3.70%)
Missing		155	205	360
Questions or concerns to discuss with the pharmacist?	85
No		80 (94.1%)	0 (NA%)	80 (94.1%)
Yes		5 (5.88%)	0 (NA%)	5 (5.88%)
Missing		97	205	302
¹ n (%)

3 AE interventions in the first 45 days of treatment

3.1 Number of interventions

Characteristic	N	Study assignment		Overall, N = 387¹
Characteristic	N	Case, N = 182¹	Control, N = 205¹	Overall, N = 387¹
Any AE intervention	387
No		141 (77.5%)	167 (81.5%)	308 (79.6%)
Yes		41 (22.5%)	38 (18.5%)	79 (20.4%)
Number of AE interventions	387
0		141 (77.5%)	167 (81.5%)	308 (79.6%)
1		29 (15.9%)	30 (14.6%)	59 (15.2%)
2		10 (5.49%)	6 (2.93%)	16 (4.13%)
3		0 (0%)	2 (0.98%)	2 (0.52%)
4		1 (0.55%)	0 (0%)	1 (0.26%)
6		1 (0.55%)	0 (0%)	1 (0.26%)
¹ n (%)

3.2 Intervention details

Characteristic	N	Study assignment		Overall, N = 107¹
Characteristic	N	Case, N = 59¹	Control, N = 48¹	Overall, N = 107¹
Did action take place regarding the alert?	107
No		0 (0%)	2 (4.17%)	2 (1.87%)
Yes		59 (100.0%)	46 (95.8%)	105 (98.1%)
Was there a recommendation made to the provider?	105
No		57 (96.6%)	43 (93.5%)	100 (95.2%)
Yes		2 (3.39%)	3 (6.52%)	5 (4.76%)
Missing		0	2	2
What was the pharmacist's health outcomes impact?	105
No risk		30 (50.8%)	24 (52.2%)	54 (51.4%)
Low risk		26 (44.1%)	19 (41.3%)	45 (42.9%)
Moderate risk		3 (5.08%)	3 (6.52%)	6 (5.71%)
High risk		0 (0%)	0 (0%)	0 (0%)
Missing		0	2	2
How long did the pharmacist spend on the intervention?	105
Mean (SD)		13.0 (11.4)	12.6 (7.7)	12.8 (9.9)
Median (IQR)		10.0 (6.0 - 15.0)	10.0 (7.0 - 15.0)	10.0 (6.0 - 15.0)
Range		2.0 - 55.0	5.0 - 40.0	2.0 - 55.0
Missing		0	2	2
¹ n (%)

3.3 Time to first AE intervention

Characteristic	N	Study assignment		Overall, N = 387
Characteristic	N	Case, N = 182	Control, N = 205	Overall, N = 387
Time from counseling to first AE intervention	79
Mean (SD)		18.6 (8.6)	24.0 (9.2)	21.2 (9.3)
Median (IQR)		19.0 (12.0 - 25.0)	24.5 (22.0 - 28.8)	22.0 (14.0 - 27.0)
Range		2.0 - 41.0	4.0 - 43.0	2.0 - 43.0
Missing		141	167	308

3.4 Type and outcomes of interventions within 45 days

3.5 Actions

Characteristic	Study assignment		Overall, N = 79¹
Characteristic	Case, N = 41¹	Control, N = 38¹	Overall, N = 79¹
Chart/labs/medical documentation reviewed and/or updated	31 (75.6%)	33 (86.8%)	64 (81.0%)
education tools or material provided	1 (2.44%)	0 (0%)	1 (1.27%)
financial/ insurance counseling provided	1 (2.44%)	0 (0%)	1 (1.27%)
Medication reconciliation performed	1 (2.44%)	5 (13.2%)	6 (7.59%)
Patient Counseling provided	30 (73.2%)	24 (63.2%)	54 (68.4%)
prescriber contacted - no recommendation made	5 (12.2%)	6 (15.8%)	11 (13.9%)
Referred for clinic appointment or internal provider	1 (2.44%)	0 (0%)	1 (1.27%)
[Zero selected]	0 (0%)	2 (5.26%)	2 (2.53%)
¹ n (%)

Characteristic	N	Study assignment		Overall, N = 174¹
Characteristic	N	Case, N = 93¹	Control, N = 81¹	Overall, N = 174¹
Action	174
Chart/labs/medical documentation reviewed and/or updated		35 (37.6%)	40 (49.4%)	75 (43.1%)
Patient Counseling provided		46 (49.5%)	29 (35.8%)	75 (43.1%)
prescriber contacted - no recommendation made		8 (8.60%)	7 (8.64%)	15 (8.62%)
Medication reconciliation performed		1 (1.08%)	5 (6.17%)	6 (3.45%)
education tools or material provided		1 (1.08%)	0 (0%)	1 (0.57%)
financial/ insurance counseling provided		1 (1.08%)	0 (0%)	1 (0.57%)
Referred for clinic appointment or internal provider		1 (1.08%)	0 (0%)	1 (0.57%)
¹ n (%)

Characteristic	Study assignment		Overall, N = 79¹
Characteristic	Case, N = 41¹	Control, N = 38¹	Overall, N = 79¹
Number of observations (rows)
1	29 (70.7%)	30 (78.9%)	59 (74.7%)
2	10 (24.4%)	6 (15.8%)	16 (20.3%)
3	0 (0%)	2 (5.26%)	2 (2.53%)
4	1 (2.44%)	0 (0%)	1 (1.27%)
6	1 (2.44%)	0 (0%)	1 (1.27%)
No selections made across all observations	0 (0%)	2 (5.26%)	2 (2.53%)
Number of selections made
0	0 (0%)	2 (5.26%)	2 (2.53%)
1	14 (34.1%)	12 (31.6%)	26 (32.9%)
2	17 (41.5%)	14 (36.8%)	31 (39.2%)
3	5 (12.2%)	4 (10.5%)	9 (11.4%)
4	3 (7.32%)	2 (5.26%)	5 (6.33%)
5	0 (0%)	3 (7.89%)	3 (3.80%)
6	0 (0%)	1 (2.63%)	1 (1.27%)
8	1 (2.44%)	0 (0%)	1 (1.27%)
10	1 (2.44%)	0 (0%)	1 (1.27%)
Number of unique selections made
0	0 (0%)	2 (5.26%)	2 (2.53%)
1	17 (41.5%)	13 (34.2%)	30 (38.0%)
2	19 (46.3%)	15 (39.5%)	34 (43.0%)
3	5 (12.2%)	7 (18.4%)	12 (15.2%)
4	0 (0%)	1 (2.63%)	1 (1.27%)
¹ n (%)

3.6 Intervention outcomes

Characteristic	Assignment		Overall, N = 79¹
Characteristic	Case, N = 41¹	Control, N = 38¹	Overall, N = 79¹
identified issue resolved	37 (90.2%)	31 (81.6%)	68 (86.1%)
identified issue unresolved	3 (7.32%)	6 (15.8%)	9 (11.4%)
Adjunct therapy started	4 (9.76%)	0 (0%)	4 (5.06%)
follow up care scheduled (lab/appointment)	2 (4.88%)	2 (5.26%)	4 (5.06%)
medication administration held	2 (4.88%)	2 (5.26%)	4 (5.06%)
dosage adjustment made	0 (0%)	1 (2.63%)	1 (1.27%)
[Zero selected]	0 (0%)	2 (5.26%)	2 (2.53%)
¹ n (%)

Characteristic	N	Assignment		Overall, N = 115¹
Characteristic	N	Case, N = 64¹	Control, N = 51¹	Overall, N = 115¹
Outcome intervention	115
identified issue resolved		51 (79.7%)	38 (74.5%)	89 (77.4%)
identified issue unresolved		3 (4.69%)	6 (11.8%)	9 (7.83%)
Adjunct therapy started		5 (7.81%)	0 (0%)	5 (4.35%)
follow up care scheduled (lab/appointment)		2 (3.13%)	2 (3.92%)	4 (3.48%)
medication administration held		2 (3.13%)	2 (3.92%)	4 (3.48%)
[Zero selected]		1 (1.56%)	2 (3.92%)	3 (2.61%)
dosage adjustment made		0 (0%)	1 (1.96%)	1 (0.87%)
¹ n (%)

Characteristic	Assignment		Overall, N = 107¹
Characteristic	Case, N = 59¹	Control, N = 48¹	Overall, N = 107¹
identified issue resolved	51 (86.4%)	38 (79.2%)	89 (83.2%)
identified issue unresolved	3 (5.08%)	6 (12.5%)	9 (8.41%)
Adjunct therapy started	5 (8.47%)	0 (0%)	5 (4.67%)
follow up care scheduled (lab/appointment)	2 (3.39%)	2 (4.17%)	4 (3.74%)
medication administration held	2 (3.39%)	2 (4.17%)	4 (3.74%)
dosage adjustment made	0 (0%)	1 (2.08%)	1 (0.93%)
[Zero selected]	1 (1.69%)	2 (4.17%)	3 (2.80%)
¹ n (%)

3.7 Category for alert

Characteristic	N	Assignment		Overall, N = 145¹
Characteristic	N	Case, N = 77¹	Control, N = 68¹	Overall, N = 145¹
Category for alert	145
Adverse event/toxicity		59 (76.6%)	48 (70.6%)	107 (73.8%)
Adherence		7 (9.09%)	8 (11.8%)	15 (10.3%)
Medication reconciliation/interaction		3 (3.90%)	7 (10.3%)	10 (6.90%)
Drug admin/dosing question		4 (5.19%)	1 (1.47%)	5 (3.45%)
ED/hospitalization/urgent care visit		2 (2.60%)	3 (4.41%)	5 (3.45%)
Coordination of care		2 (2.60%)	1 (1.47%)	3 (2.07%)
¹ n (%)

Characteristic	Assignment		Overall, N = 79¹
Characteristic	Case, N = 41¹	Control, N = 38¹	Overall, N = 79¹
Adverse event/toxicity
Yes	41 (100.0%)	38 (100.0%)	79 (100.0%)
Adherence	6 (14.6%)	7 (18.4%)	13 (16.5%)
Medication reconciliation/interaction	3 (7.32%)	6 (15.8%)	9 (11.4%)
Drug admin/dosing question	4 (9.76%)	1 (2.63%)	5 (6.33%)
ED/hospitalization/urgent care visit	2 (4.88%)	3 (7.89%)	5 (6.33%)
Coordination of care	2 (4.88%)	1 (2.63%)	3 (3.80%)
¹ n (%)

Characteristic	Assignment		Overall, N = 107¹
Characteristic	Case, N = 59¹	Control, N = 48¹	Overall, N = 107¹
Adverse event/toxicity
Yes	59 (100.0%)	48 (100.0%)	107 (100.0%)
Adherence	7 (11.9%)	8 (16.7%)	15 (14.0%)
Medication reconciliation/interaction	3 (5.08%)	7 (14.6%)	10 (9.35%)
Drug admin/dosing question	4 (6.78%)	1 (2.08%)	5 (4.67%)
ED/hospitalization/urgent care visit	2 (3.39%)	3 (6.25%)	5 (4.67%)
Coordination of care	2 (3.39%)	1 (2.08%)	3 (2.80%)
¹ n (%)

4 Analysis

ITT is the entire cohort, comparing those randomized to treatment vs those randomized to usual care

mITT is the entire cohort, comparing those who responded vs those who did not

Per protocol is case responders and all controls, comparing those who responded vs those who did not

4.1 Time to intervention

Cox Proportional Hazards Regression: results are presented on hazard ratio (HR) scale. For a HR of 2.0 (group A vs group B), the interpretation would be: Patients in group A are two times more likely to receive their initial pharmacist (or AE) intervention as compared to group B.

Censoring

Patients are censored if they do not have an AE intervention within 45 days of dispense date.

Time to event

The event is calculated as time from date of dispense to first AE intervention date.

Characteristic	N	PharmD Intervention		Overall, N = 387¹
Characteristic	N	No, N = 308¹	Yes, N = 79¹	Overall, N = 387¹
Questionnaire response	387
Yes		53 (17.2%)	32 (40.5%)	85 (22.0%)
No		255 (82.8%)	47 (59.5%)	302 (78.0%)
Sex	387
Female		128 (41.6%)	32 (40.5%)	160 (41.3%)
Male		180 (58.4%)	47 (59.5%)	227 (58.7%)
Age group	387
< 60		102 (33.1%)	18 (22.8%)	120 (31.0%)
>= 60		206 (66.9%)	61 (77.2%)	267 (69.0%)
Charlson Comorbidity Index Score	387
Mean (SD)		7.1 (2.7)	7.0 (2.8)	7.1 (2.7)
Median (IQR)		7.0 (5.0 - 9.0)	7.0 (4.5 - 9.0)	7.0 (5.0 - 9.0)
Range		0.0 - 16.0	2.0 - 15.0	0.0 - 16.0
tte_ae	387
Mean (SD)		45.0 (0.0)	21.2 (9.3)	40.1 (10.5)
Median (IQR)		45.0 (45.0 - 45.0)	22.0 (14.0 - 27.0)	45.0 (45.0 - 45.0)
Range		45.0 - 45.0	2.0 - 43.0	2.0 - 45.0
Time from counseling to first AE intervention	79
Mean (SD)		NA (NA)	21.2 (9.3)	21.2 (9.3)
Median (IQR)		NA (NA - NA)	22.0 (14.0 - 27.0)	22.0 (14.0 - 27.0)
Range		Inf - -Inf	2.0 - 43.0	2.0 - 43.0
Missing		308	0	308
Drug class category	387
Anti-androgens/hormone receptor antagonists		96 (31.2%)	33 (41.8%)	129 (33.3%)
Anti-neoplastic agents		212 (68.8%)	46 (58.2%)	258 (66.7%)
Diagnosis category	387
Breast		53 (17.2%)	9 (11.4%)	62 (16.0%)
Central nervous system		37 (12.0%)	7 (8.86%)	44 (11.4%)
GI		47 (15.3%)	11 (13.9%)	58 (15.0%)
GU		125 (40.6%)	39 (49.4%)	164 (42.4%)
GYN		4 (1.30%)	1 (1.27%)	5 (1.29%)
Head/neck		8 (2.60%)	1 (1.27%)	9 (2.33%)
Lung		16 (5.19%)	3 (3.80%)	19 (4.91%)
Melanoma/sarcoma		18 (5.84%)	8 (10.1%)	26 (6.72%)
What is the patient's cancer stage?	387
stage I		15 (4.87%)	2 (2.53%)	17 (4.39%)
stage II		34 (11.0%)	15 (19.0%)	49 (12.7%)
stage III		53 (17.2%)	13 (16.5%)	66 (17.1%)
stage IV		202 (65.6%)	47 (59.5%)	249 (64.3%)
staging not available		4 (1.30%)	2 (2.53%)	6 (1.55%)
¹ n (%)

[![](figures/ae_km.png)](figures/ae_km.png)

Characteristic	N	HR¹	95% CI¹	p-value
Study assignment	387
Case		—	—
Control		0.77	0.50, 1.20	0.2
Sex	387
Female		—	—
Male		1.02	0.65, 1.61	>0.9
Age group	387
< 60		—	—
>= 60		1.60	0.95, 2.71	0.079
Charlson Comorbidity Index Score	387	0.99	0.91, 1.07	0.7
Drug class category	387
Anti-androgens/hormone receptor antagonists		—	—
Anti-neoplastic agents		0.67	0.43, 1.04	0.075
Diagnosis category	387
Breast		—	—
Central nervous system		1.15	0.43, 3.10	0.8
GI		1.39	0.58, 3.35	0.5
GU		1.71	0.83, 3.54	0.14
GYN		1.39	0.18, 11.0	0.8
Head/neck		0.77	0.10, 6.07	0.8
Lung		1.08	0.29, 3.99	>0.9
Melanoma/sarcoma		2.37	0.91, 6.14	0.076
What is the patient's cancer stage?	387
stage I		—	—
stage II		3.07	0.70, 13.4	0.14
stage III		1.76	0.40, 7.80	0.5
stage IV		1.69	0.41, 6.95	0.5
staging not available		3.11	0.44, 22.1	0.3
Questionnaire response	387
Yes		—	—
No		0.33	0.21, 0.52	<0.001
¹ HR = Hazard Ratio, CI = Confidence Interval

label	levels	effect	conf.low	conf.high	d.f.	P
Treatment assignment	Case vs. Control	1.239	0.792	1.938	1	0.347
Charlson index	9 vs. 5	0.814	0.559	1.184	1	0.281
Sex	Female vs. Male	1.359	0.746	2.475	1	0.316
Age group	< 60 vs. >= 60	0.583	0.318	1.067	1	0.080
Medication category	Anti-androgens/hormone receptor antagonists vs. Anti-neoplastic agents	1.574	0.851	2.910	1	0.148

Cox Proportional Hazards Model

cph(formula = Surv(tte_ae, event_ae) ~ assignment + charlson + 
    r_sex + r_age_group + med_recat, data = oa)

	Model Tests	Discrimination Indexes
Obs 387	LR χ² 8.61	R² 0.024
Events 79	d.f. 5	R²_5,387 0.009
Center -0.5881	Pr(>χ²) 0.1255	R²_5,79 0.045
	Score χ² 8.45	D_xy 0.201
	Pr(>χ²) 0.1332

	β	S.E.	Wald Z	Pr(>\|Z\|)
assignment=Control	-0.2145	0.2282	-0.94	0.3472
charlson	-0.0515	0.0478	-1.08	0.2810
r_sex=Male	-0.3068	0.3057	-1.00	0.3156
r_age_group=≥ 60	0.5399	0.3087	1.75	0.0804
med_recat=Anti-neoplastic agents	-0.4536	0.3136	-1.45	0.1480

Censoring

Patients are censored if they do not have an AE intervention within 45 days of dispense date.

Time to event

The event is calculated as time from date of dispense to first AE intervention date.

Characteristic	N	PharmD Intervention		Overall, N = 387¹
Characteristic	N	No, N = 308¹	Yes, N = 79¹	Overall, N = 387¹
Questionnaire response	387
Yes		53 (17.2%)	32 (40.5%)	85 (22.0%)
No		255 (82.8%)	47 (59.5%)	302 (78.0%)
Sex	387
Female		128 (41.6%)	32 (40.5%)	160 (41.3%)
Male		180 (58.4%)	47 (59.5%)	227 (58.7%)
Age group	387
< 60		102 (33.1%)	18 (22.8%)	120 (31.0%)
>= 60		206 (66.9%)	61 (77.2%)	267 (69.0%)
Charlson Comorbidity Index Score	387
Mean (SD)		7.1 (2.7)	7.0 (2.8)	7.1 (2.7)
Median (IQR)		7.0 (5.0 - 9.0)	7.0 (4.5 - 9.0)	7.0 (5.0 - 9.0)
Range		0.0 - 16.0	2.0 - 15.0	0.0 - 16.0
tte_ae	387
Mean (SD)		45.0 (0.0)	21.2 (9.3)	40.1 (10.5)
Median (IQR)		45.0 (45.0 - 45.0)	22.0 (14.0 - 27.0)	45.0 (45.0 - 45.0)
Range		45.0 - 45.0	2.0 - 43.0	2.0 - 45.0
Time from counseling to first AE intervention	79
Mean (SD)		NA (NA)	21.2 (9.3)	21.2 (9.3)
Median (IQR)		NA (NA - NA)	22.0 (14.0 - 27.0)	22.0 (14.0 - 27.0)
Range		Inf - -Inf	2.0 - 43.0	2.0 - 43.0
Missing		308	0	308
Drug class category	387
Anti-androgens/hormone receptor antagonists		96 (31.2%)	33 (41.8%)	129 (33.3%)
Anti-neoplastic agents		212 (68.8%)	46 (58.2%)	258 (66.7%)
Diagnosis category	387
Breast		53 (17.2%)	9 (11.4%)	62 (16.0%)
Central nervous system		37 (12.0%)	7 (8.86%)	44 (11.4%)
GI		47 (15.3%)	11 (13.9%)	58 (15.0%)
GU		125 (40.6%)	39 (49.4%)	164 (42.4%)
GYN		4 (1.30%)	1 (1.27%)	5 (1.29%)
Head/neck		8 (2.60%)	1 (1.27%)	9 (2.33%)
Lung		16 (5.19%)	3 (3.80%)	19 (4.91%)
Melanoma/sarcoma		18 (5.84%)	8 (10.1%)	26 (6.72%)
What is the patient's cancer stage?	387
stage I		15 (4.87%)	2 (2.53%)	17 (4.39%)
stage II		34 (11.0%)	15 (19.0%)	49 (12.7%)
stage III		53 (17.2%)	13 (16.5%)	66 (17.1%)
stage IV		202 (65.6%)	47 (59.5%)	249 (64.3%)
staging not available		4 (1.30%)	2 (2.53%)	6 (1.55%)
¹ n (%)

Characteristic	N	HR¹	95% CI¹	p-value
Study assignment	387
Case		—	—
Control		0.77	0.50, 1.20	0.2
Sex	387
Female		—	—
Male		1.02	0.65, 1.61	>0.9
Age group	387
< 60		—	—
>= 60		1.60	0.95, 2.71	0.079
Charlson Comorbidity Index Score	387	0.99	0.91, 1.07	0.7
Drug class category	387
Anti-androgens/hormone receptor antagonists		—	—
Anti-neoplastic agents		0.67	0.43, 1.04	0.075
Diagnosis category	387
Breast		—	—
Central nervous system		1.15	0.43, 3.10	0.8
GI		1.39	0.58, 3.35	0.5
GU		1.71	0.83, 3.54	0.14
GYN		1.39	0.18, 11.0	0.8
Head/neck		0.77	0.10, 6.07	0.8
Lung		1.08	0.29, 3.99	>0.9
Melanoma/sarcoma		2.37	0.91, 6.14	0.076
What is the patient's cancer stage?	387
stage I		—	—
stage II		3.07	0.70, 13.4	0.14
stage III		1.76	0.40, 7.80	0.5
stage IV		1.69	0.41, 6.95	0.5
staging not available		3.11	0.44, 22.1	0.3
Questionnaire response	387
Yes		—	—
No		0.33	0.21, 0.52	<0.001
¹ HR = Hazard Ratio, CI = Confidence Interval

label	levels	effect	conf.low	conf.high	d.f.	P
Questionnaire response	Yes vs. No	2.867	1.787	4.602	1	<0.001
Charlson index	9 vs. 5	0.885	0.604	1.299	1	0.533
Sex	Female vs. Male	1.403	0.767	2.566	1	0.272
Age group	< 60 vs. >= 60	0.599	0.325	1.103	1	0.100
Medication category	Anti-androgens/hormone receptor antagonists vs. Anti-neoplastic agents	1.286	0.684	2.420	1	0.435

Cox Proportional Hazards Model

cph(formula = Surv(tte_ae, event_ae) ~ questionnaire_response + 
    charlson + r_sex + r_age_group + med_recat, data = oa)

	Model Tests	Discrimination Indexes
Obs 387	LR χ² 25.26	R² 0.070
Events 79	d.f. 5	R²_5,387 0.051
Center -1.0504	Pr(>χ²) 0.0001	R²_5,79 0.226
	Score χ² 29.69	D_xy 0.322
	Pr(>χ²) 0.0000

	β	S.E.	Wald Z	Pr(>\|Z\|)
questionnaire_response=No	-1.0534	0.2413	-4.37	<0.0001
charlson	-0.0304	0.0489	-0.62	0.5332
r_sex=Male	-0.3386	0.3080	-1.10	0.2716
r_age_group=≥ 60	0.5125	0.3117	1.64	0.1002
med_recat=Anti-neoplastic agents	-0.2519	0.3224	-0.78	0.4346

Censoring

Patients are censored if they do not have an AE intervention within 45 days of dispense date.

Time to event

The event is calculated as time from date of dispense to first AE intervention date.

Characteristic	N	PharmD Intervention		Overall, N = 290¹
Characteristic	N	No, N = 220¹	Yes, N = 70¹	Overall, N = 290¹
Questionnaire response	290
Yes		53 (24.1%)	32 (45.7%)	85 (29.3%)
No		167 (75.9%)	38 (54.3%)	205 (70.7%)
Sex	290
Female		87 (39.5%)	28 (40.0%)	115 (39.7%)
Male		133 (60.5%)	42 (60.0%)	175 (60.3%)
Age group	290
< 60		68 (30.9%)	17 (24.3%)	85 (29.3%)
>= 60		152 (69.1%)	53 (75.7%)	205 (70.7%)
Charlson Comorbidity Index Score	290
Mean (SD)		7.1 (2.7)	7.1 (2.8)	7.1 (2.7)
Median (IQR)		7.0 (5.0 - 9.0)	7.0 (5.0 - 9.8)	7.0 (5.0 - 9.0)
Range		0.0 - 14.0	2.0 - 15.0	0.0 - 15.0
tte_ae	290
Mean (SD)		45.0 (0.0)	21.0 (9.4)	39.2 (11.3)
Median (IQR)		45.0 (45.0 - 45.0)	22.0 (13.3 - 27.0)	45.0 (45.0 - 45.0)
Range		45.0 - 45.0	2.0 - 43.0	2.0 - 45.0
Time from counseling to first AE intervention	70
Mean (SD)		NA (NA)	21.0 (9.4)	21.0 (9.4)
Median (IQR)		NA (NA - NA)	22.0 (13.3 - 27.0)	22.0 (13.3 - 27.0)
Range		Inf - -Inf	2.0 - 43.0	2.0 - 43.0
Missing		220	0	220
Drug class category	290
Anti-androgens/hormone receptor antagonists		74 (33.6%)	29 (41.4%)	103 (35.5%)
Anti-neoplastic agents		146 (66.4%)	41 (58.6%)	187 (64.5%)
Diagnosis category	290
Breast		34 (15.5%)	7 (10.0%)	41 (14.1%)
Central nervous system		24 (10.9%)	6 (8.57%)	30 (10.3%)
GI		37 (16.8%)	10 (14.3%)	47 (16.2%)
GU		94 (42.7%)	34 (48.6%)	128 (44.1%)
GYN		3 (1.36%)	1 (1.43%)	4 (1.38%)
Head/neck		6 (2.73%)	1 (1.43%)	7 (2.41%)
Lung		13 (5.91%)	3 (4.29%)	16 (5.52%)
Melanoma/sarcoma		9 (4.09%)	8 (11.4%)	17 (5.86%)
What is the patient's cancer stage?	290
stage I		11 (5.00%)	0 (0%)	11 (3.79%)
stage II		26 (11.8%)	13 (18.6%)	39 (13.4%)
stage III		35 (15.9%)	11 (15.7%)	46 (15.9%)
stage IV		145 (65.9%)	44 (62.9%)	189 (65.2%)
staging not available		3 (1.36%)	2 (2.86%)	5 (1.72%)
¹ n (%)

[![](figures/qr_km.png)](figures/qr_km.png)

Characteristic	N	HR¹	95% CI¹	p-value
Questionnaire response	290
Yes		—	—
No		0.40	0.25, 0.65	<0.001
Sex	290
Female		—	—
Male		0.97	0.60, 1.57	>0.9
Age group	290
< 60		—	—
>= 60		1.35	0.78, 2.33	0.3
Charlson Comorbidity Index Score	290	0.99	0.91, 1.08	0.9
Drug class category	290
Anti-androgens/hormone receptor antagonists		—	—
Anti-neoplastic agents		0.74	0.46, 1.20	0.2
Diagnosis category	290
Breast		—	—
Central nervous system		1.26	0.42, 3.76	0.7
GI		1.32	0.50, 3.46	0.6
GU		1.64	0.73, 3.69	0.2
GYN		1.49	0.18, 12.1	0.7
Head/neck		0.84	0.10, 6.87	0.9
Lung		1.09	0.28, 4.20	>0.9
Melanoma/sarcoma		3.39	1.23, 9.34	0.018
¹ HR = Hazard Ratio, CI = Confidence Interval

Cancer stage model does not converge

label	levels	effect	conf.low	conf.high	d.f.	P
Questionnaire response	Yes vs. No	2.463	1.500	4.046	1	<0.001
Charlson index	9 vs. 5	0.991	0.656	1.496	1	0.965
Sex	Female vs. Male	1.405	0.742	2.661	1	0.296
Age group	< 60 vs. >= 60	0.736	0.390	1.390	1	0.345
Medication category	Anti-androgens/hormone receptor antagonists vs. Anti-neoplastic agents	1.234	0.634	2.403	1	0.536

Cox Proportional Hazards Model

cph(formula = Surv(tte_ae, event_ae) ~ questionnaire_response + 
    charlson + r_sex + r_age_group + med_recat, data = oa %>% 
    filter(per_protocol == "Yes"))

	Model Tests	Discrimination Indexes
Obs 290	LR χ² 15.74	R² 0.057
Events 70	d.f. 5	R²_5,290 0.036
Center -0.778	Pr(>χ²) 0.0076	R²_5,70 0.142
	Score χ² 17.39	D_xy 0.272
	Pr(>χ²) 0.0038

	β	S.E.	Wald Z	Pr(>\|Z\|)
questionnaire_response=No	-0.9016	0.2531	-3.56	0.0004
charlson	-0.0023	0.0525	-0.04	0.9654
r_sex=Male	-0.3403	0.3256	-1.05	0.2960
r_age_group=≥ 60	0.3063	0.3243	0.94	0.3449
med_recat=Anti-neoplastic agents	-0.2102	0.3400	-0.62	0.5363

4.2 Number of interventions

Proportional Odds Logistic Regression: results are presented on odds ratio (OR) scale. For an OR of 2.0 (group A vs group B), the interpretation would be: Patients in group A are two times more likely to have a higher number of pharmacist (or AE) interventions as compared to group B.

Characteristic	N	Questionnaire response		p-value²	Overall, N = 387¹
Characteristic	N	Case, N = 182¹	Control, N = 205¹	p-value²	Overall, N = 387¹
Number of AE interventions	387			0.306
0		141 (77.5%)	167 (81.5%)		308 (79.6%)
1		29 (15.9%)	30 (14.6%)		59 (15.2%)
2		10 (5.49%)	6 (2.93%)		16 (4.13%)
3		0 (0%)	2 (0.98%)		2 (0.52%)
4		1 (0.55%)	0 (0%)		1 (0.26%)
6		1 (0.55%)	0 (0%)		1 (0.26%)
Number of AE interventions (categorized)	387			0.587
0		141 (77.5%)	167 (81.5%)		308 (79.6%)
1		29 (15.9%)	30 (14.6%)		59 (15.2%)
2		10 (5.49%)	6 (2.93%)		16 (4.13%)
3 or more		2 (1.10%)	2 (0.98%)		4 (1.03%)
Any AE intervention	387			0.331
No		141 (77.5%)	167 (81.5%)		308 (79.6%)
Yes		41 (22.5%)	38 (18.5%)		79 (20.4%)
¹ n (%)
² Fisher’s exact test; Pearson’s Chi-squared test

Row-wise percentages

Characteristic	N	AE Interventions				Overall, N = 387¹
Characteristic	N	0, N = 308¹	1, N = 59¹	2, N = 16¹	3 or more, N = 4¹	Overall, N = 387¹
Study assignment	387
Case		141 (77.5%)	29 (15.9%)	10 (5.49%)	2 (1.10%)	182 (100.0%)
Control		167 (81.5%)	30 (14.6%)	6 (2.93%)	2 (0.98%)	205 (100.0%)
Sex	387
Female		128 (80.0%)	20 (12.5%)	9 (5.63%)	3 (1.88%)	160 (100.0%)
Male		180 (79.3%)	39 (17.2%)	7 (3.08%)	1 (0.44%)	227 (100.0%)
Age group	387
< 60		102 (85.0%)	12 (10.0%)	4 (3.33%)	2 (1.67%)	120 (100.0%)
>= 60		206 (77.2%)	47 (17.6%)	12 (4.49%)	2 (0.75%)	267 (100.0%)
Charlson Comorbidity Index Score	387
Mean (SD)		7.1 (2.7)	6.8 (2.7)	7.5 (3.3)	8.0 (3.4)	7.1 (2.7)
Median (IQR)		7.0 (5.0 - 9.0)	7.0 (4.0 - 9.0)	7.5 (5.0 - 10.0)	8.0 (6.3 - 9.8)	7.0 (5.0 - 9.0)
Range		0.0 - 16.0	2.0 - 12.0	2.0 - 15.0	4.0 - 12.0	0.0 - 16.0
Drug class category	387
Anti-androgens/hormone receptor antagonists		96 (74.4%)	28 (21.7%)	5 (3.88%)	0 (0%)	129 (100.0%)
Anti-neoplastic agents		212 (82.2%)	31 (12.0%)	11 (4.26%)	4 (1.55%)	258 (100.0%)
Diagnosis category	387
Breast		53 (85.5%)	6 (9.68%)	2 (3.23%)	1 (1.61%)	62 (100.0%)
Central nervous system		37 (84.1%)	5 (11.4%)	2 (4.55%)	0 (0%)	44 (100.0%)
GI		47 (81.0%)	6 (10.3%)	3 (5.17%)	2 (3.45%)	58 (100.0%)
GU		125 (76.2%)	33 (20.1%)	5 (3.05%)	1 (0.61%)	164 (100.0%)
GYN		4 (80.0%)	1 (20.0%)	0 (0%)	0 (0%)	5 (100.0%)
Head/neck		8 (88.9%)	1 (11.1%)	0 (0%)	0 (0%)	9 (100.0%)
Lung		16 (84.2%)	3 (15.8%)	0 (0%)	0 (0%)	19 (100.0%)
Melanoma/sarcoma		18 (69.2%)	4 (15.4%)	4 (15.4%)	0 (0%)	26 (100.0%)
What is the patient's cancer stage?	387
stage I		15 (88.2%)	2 (11.8%)	0 (0%)	0 (0%)	17 (100.0%)
stage II		34 (69.4%)	12 (24.5%)	3 (6.12%)	0 (0%)	49 (100.0%)
stage III		53 (80.3%)	11 (16.7%)	1 (1.52%)	1 (1.52%)	66 (100.0%)
stage IV		202 (81.1%)	32 (12.9%)	12 (4.82%)	3 (1.20%)	249 (100.0%)
staging not available		4 (66.7%)	2 (33.3%)	0 (0%)	0 (0%)	6 (100.0%)
¹ n (%)

Characteristic	N	OR¹	95% CI¹	p-value
Questionnaire response	387
Yes		—	—
No		0.30	0.17, 0.51	<0.001
Sex	387
Female		—	—
Male		0.99	0.60, 1.64	>0.9
Age group	387
< 60		—	—
>= 60		1.63	0.93, 2.97	0.10
Charlson Comorbidity Index Score	387	0.99	0.91, 1.09	0.8
Drug class category	387
Anti-androgens/hormone receptor antagonists		—	—
Anti-neoplastic agents		0.67	0.41, 1.11	0.12
Diagnosis category	387
Breast		—	—
Central nervous system		1.10	0.36, 3.21	0.9
GI		1.43	0.55, 3.84	0.5
GU		1.75	0.82, 4.07	0.2
GYN		1.36	0.07, 10.2	0.8
Head/neck		0.70	0.04, 4.51	0.8
Lung		1.04	0.21, 3.94	>0.9
Melanoma/sarcoma		2.81	0.93, 8.43	0.064
cancer_stage	387
stage II		—	—
stage I		0.30	0.04, 1.25	0.14
stage III		0.57	0.24, 1.32	0.2
stage IV		0.56	0.29, 1.12	0.089
staging not available		1.03	0.14, 5.35	>0.9
¹ OR = Odds Ratio, CI = Confidence Interval

label	levels	effect	conf.low	conf.high	d.f.	P
Treatment assignment	Case vs. Control	1.245	0.753	2.058	1	0.394
Charlson index	9 vs. 5	0.855	0.565	1.292	1	0.456
Sex	Female vs. Male	1.405	0.731	2.703	1	0.308
Age group	< 60 vs. >= 60	0.599	0.309	1.162	1	0.130
Medication category	Anti-androgens/hormone receptor antagonists vs. Anti-neoplastic agents	1.579	0.801	3.116	1	0.187

Logistic (Proportional Odds) Ordinal Regression Model

orm(formula = n_ae_interventions ~ assignment + charlson + r_sex + 
    r_age_group + med_recat, data = oa)

Frequencies of Responses

  0   1   2   3   4   6 
308  59  16   2   1   1

	Model Likelihood Ratio Test	Discrimination Indexes	Rank Discrim. Indexes
Obs 387	LR χ² 6.87	R² 0.024	ρ 0.141
Distinct Y 6	d.f. 5	R²_5,387 0.005
Y_0.5 0	Pr(>χ²) 0.2302	R²_5,190.5 0.010
max \|∂log L/∂β\| 7×10^-5	Score χ² 6.70	\|Pr(Y ≥ median)-½\| 0.297
	Pr(>χ²) 0.2441

	β	S.E.	Wald Z	Pr(>\|Z\|)
y≥1	-0.8546	0.5258	-1.63	0.1041
y≥2	-2.4233	0.5564	-4.36	<0.0001
y≥3	-4.0754	0.7138	-5.71	<0.0001
y≥4	-4.7727	0.8714	-5.48	<0.0001
y≥6	-5.4685	1.1222	-4.87	<0.0001
assignment=Control	-0.2189	0.2566	-0.85	0.3936
charlson	-0.0392	0.0527	-0.74	0.4565
r_sex=Male	-0.3403	0.3338	-1.02	0.3079
r_age_group=≥ 60	0.5128	0.3384	1.52	0.1297
med_recat=Anti-neoplastic agents	-0.4570	0.3467	-1.32	0.1874

Characteristic	N	Questionnaire response		p-value²	Overall, N = 387¹
Characteristic	N	Yes, N = 85¹	No, N = 302¹	p-value²	Overall, N = 387¹
Number of AE interventions	387			<0.001
0		53 (62.4%)	255 (84.4%)		308 (79.6%)
1		21 (24.7%)	38 (12.6%)		59 (15.2%)
2		10 (11.8%)	6 (1.99%)		16 (4.13%)
3		0 (0%)	2 (0.66%)		2 (0.52%)
4		1 (1.18%)	0 (0%)		1 (0.26%)
6		0 (0%)	1 (0.33%)		1 (0.26%)
Number of AE interventions (categorized)	387			<0.001
0		53 (62.4%)	255 (84.4%)		308 (79.6%)
1		21 (24.7%)	38 (12.6%)		59 (15.2%)
2		10 (11.8%)	6 (1.99%)		16 (4.13%)
3 or more		1 (1.18%)	3 (0.99%)		4 (1.03%)
Any AE intervention	387			<0.001
No		53 (62.4%)	255 (84.4%)		308 (79.6%)
Yes		32 (37.6%)	47 (15.6%)		79 (20.4%)
¹ n (%)
² Fisher’s exact test; Pearson’s Chi-squared test

Row-wise percentages

Characteristic	N	AE Interventions				Overall, N = 387¹
Characteristic	N	0, N = 308¹	1, N = 59¹	2, N = 16¹	3 or more, N = 4¹	Overall, N = 387¹
Questionnaire response	387
Yes		53 (62.4%)	21 (24.7%)	10 (11.8%)	1 (1.18%)	85 (100.0%)
No		255 (84.4%)	38 (12.6%)	6 (1.99%)	3 (0.99%)	302 (100.0%)
Sex	387
Female		128 (80.0%)	20 (12.5%)	9 (5.63%)	3 (1.88%)	160 (100.0%)
Male		180 (79.3%)	39 (17.2%)	7 (3.08%)	1 (0.44%)	227 (100.0%)
Age group	387
< 60		102 (85.0%)	12 (10.0%)	4 (3.33%)	2 (1.67%)	120 (100.0%)
>= 60		206 (77.2%)	47 (17.6%)	12 (4.49%)	2 (0.75%)	267 (100.0%)
Charlson Comorbidity Index Score	387
Mean (SD)		7.1 (2.7)	6.8 (2.7)	7.5 (3.3)	8.0 (3.4)	7.1 (2.7)
Median (IQR)		7.0 (5.0 - 9.0)	7.0 (4.0 - 9.0)	7.5 (5.0 - 10.0)	8.0 (6.3 - 9.8)	7.0 (5.0 - 9.0)
Range		0.0 - 16.0	2.0 - 12.0	2.0 - 15.0	4.0 - 12.0	0.0 - 16.0
Drug class category	387
Anti-androgens/hormone receptor antagonists		96 (74.4%)	28 (21.7%)	5 (3.88%)	0 (0%)	129 (100.0%)
Anti-neoplastic agents		212 (82.2%)	31 (12.0%)	11 (4.26%)	4 (1.55%)	258 (100.0%)
Diagnosis category	387
Breast		53 (85.5%)	6 (9.68%)	2 (3.23%)	1 (1.61%)	62 (100.0%)
Central nervous system		37 (84.1%)	5 (11.4%)	2 (4.55%)	0 (0%)	44 (100.0%)
GI		47 (81.0%)	6 (10.3%)	3 (5.17%)	2 (3.45%)	58 (100.0%)
GU		125 (76.2%)	33 (20.1%)	5 (3.05%)	1 (0.61%)	164 (100.0%)
GYN		4 (80.0%)	1 (20.0%)	0 (0%)	0 (0%)	5 (100.0%)
Head/neck		8 (88.9%)	1 (11.1%)	0 (0%)	0 (0%)	9 (100.0%)
Lung		16 (84.2%)	3 (15.8%)	0 (0%)	0 (0%)	19 (100.0%)
Melanoma/sarcoma		18 (69.2%)	4 (15.4%)	4 (15.4%)	0 (0%)	26 (100.0%)
What is the patient's cancer stage?	387
stage I		15 (88.2%)	2 (11.8%)	0 (0%)	0 (0%)	17 (100.0%)
stage II		34 (69.4%)	12 (24.5%)	3 (6.12%)	0 (0%)	49 (100.0%)
stage III		53 (80.3%)	11 (16.7%)	1 (1.52%)	1 (1.52%)	66 (100.0%)
stage IV		202 (81.1%)	32 (12.9%)	12 (4.82%)	3 (1.20%)	249 (100.0%)
staging not available		4 (66.7%)	2 (33.3%)	0 (0%)	0 (0%)	6 (100.0%)
¹ n (%)

Characteristic	N	OR¹	95% CI¹	p-value
Questionnaire response	387
Yes		—	—
No		0.30	0.17, 0.51	<0.001
Sex	387
Female		—	—
Male		0.99	0.60, 1.64	>0.9
Age group	387
< 60		—	—
>= 60		1.63	0.93, 2.97	0.10
Charlson Comorbidity Index Score	387	0.99	0.91, 1.09	0.8
Drug class category	387
Anti-androgens/hormone receptor antagonists		—	—
Anti-neoplastic agents		0.67	0.41, 1.11	0.12
Diagnosis category	387
Breast		—	—
Central nervous system		1.10	0.36, 3.21	0.9
GI		1.43	0.55, 3.84	0.5
GU		1.75	0.82, 4.07	0.2
GYN		1.36	0.07, 10.2	0.8
Head/neck		0.70	0.04, 4.51	0.8
Lung		1.04	0.21, 3.94	>0.9
Melanoma/sarcoma		2.81	0.93, 8.43	0.064
cancer_stage	387
stage II		—	—
stage I		0.30	0.04, 1.25	0.14
stage III		0.57	0.24, 1.32	0.2
stage IV		0.56	0.29, 1.12	0.089
staging not available		1.03	0.14, 5.35	>0.9
¹ OR = Odds Ratio, CI = Confidence Interval

label	levels	effect	conf.low	conf.high	d.f.	P
Questionnaire response	Yes vs. No	3.310	1.893	5.786	1	<0.001
Charlson index	9 vs. 5	0.929	0.609	1.418	1	0.732
Sex	Female vs. Male	1.443	0.744	2.799	1	0.278
Age group	< 60 vs. >= 60	0.607	0.308	1.198	1	0.150
Medication category	Anti-androgens/hormone receptor antagonists vs. Anti-neoplastic agents	1.255	0.621	2.538	1	0.527

Logistic (Proportional Odds) Ordinal Regression Model

orm(formula = n_ae_interventions ~ questionnaire_response + charlson + 
    r_sex + r_age_group + med_recat, data = oa)

Frequencies of Responses

  0   1   2   3   4   6 
308  59  16   2   1   1

	Model Likelihood Ratio Test	Discrimination Indexes	Rank Discrim. Indexes
Obs 387	LR χ² 23.18	R² 0.079	ρ 0.223
Distinct Y 6	d.f. 5	R²_5,387 0.046
Y_0.5 0	Pr(>χ²) 0.0003	R²_5,190.5 0.091
max \|∂log L/∂β\| 0.003	Score χ² 25.21	\|Pr(Y ≥ median)-½\| 0.295
	Pr(>χ²) 0.0001

	β	S.E.	Wald Z	Pr(>\|Z\|)
y≥1	-0.3646	0.5451	-0.67	0.5036
y≥2	-1.9892	0.5717	-3.48	0.0005
y≥3	-3.6643	0.7254	-5.05	<0.0001
y≥4	-4.3629	0.8807	-4.95	<0.0001
y≥6	-5.0594	1.1293	-4.48	<0.0001
questionnaire_response=No	-1.1969	0.2849	-4.20	<0.0001
charlson	-0.0185	0.0539	-0.34	0.7320
r_sex=Male	-0.3667	0.3381	-1.08	0.2782
r_age_group=≥ 60	0.4990	0.3469	1.44	0.1502
med_recat=Anti-neoplastic agents	-0.2273	0.3593	-0.63	0.5271

Characteristic	N	Questionnaire response		p-value²	Overall, N = 290¹
Characteristic	N	Yes, N = 85¹	No, N = 205¹	p-value²	Overall, N = 290¹
Number of AE interventions	290			<0.001
0		53 (62.4%)	167 (81.5%)		220 (75.9%)
1		21 (24.7%)	30 (14.6%)		51 (17.6%)
2		10 (11.8%)	6 (2.93%)		16 (5.52%)
3		0 (0%)	2 (0.98%)		2 (0.69%)
4		1 (1.18%)	0 (0%)		1 (0.34%)
Number of AE interventions (categorized)	290			0.001
0		53 (62.4%)	167 (81.5%)		220 (75.9%)
1		21 (24.7%)	30 (14.6%)		51 (17.6%)
2		10 (11.8%)	6 (2.93%)		16 (5.52%)
3 or more		1 (1.18%)	2 (0.98%)		3 (1.03%)
Any AE intervention	290			<0.001
No		53 (62.4%)	167 (81.5%)		220 (75.9%)
Yes		32 (37.6%)	38 (18.5%)		70 (24.1%)
¹ n (%)
² Fisher’s exact test; Pearson’s Chi-squared test

Row-wise percentages

Characteristic	N	PharmD Interventions				Overall, N = 290¹
Characteristic	N	0, N = 220¹	1, N = 51¹	2, N = 16¹	3 or more, N = 3¹	Overall, N = 290¹
Questionnaire response	290
Yes		53 (62.4%)	21 (24.7%)	10 (11.8%)	1 (1.18%)	85 (100.0%)
No		167 (81.5%)	30 (14.6%)	6 (2.93%)	2 (0.98%)	205 (100.0%)
Sex	290
Female		87 (75.7%)	17 (14.8%)	9 (7.83%)	2 (1.74%)	115 (100.0%)
Male		133 (76.0%)	34 (19.4%)	7 (4.00%)	1 (0.57%)	175 (100.0%)
Age group	290
< 60		68 (80.0%)	11 (12.9%)	4 (4.71%)	2 (2.35%)	85 (100.0%)
>= 60		152 (74.1%)	40 (19.5%)	12 (5.85%)	1 (0.49%)	205 (100.0%)
Charlson Comorbidity Index Score	290
Mean (SD)		7.1 (2.7)	6.9 (2.7)	7.5 (3.3)	7.7 (4.0)	7.1 (2.7)
Median (IQR)		7.0 (5.0 - 9.0)	7.0 (4.5 - 9.0)	7.5 (5.0 - 10.0)	7.0 (5.5 - 9.5)	7.0 (5.0 - 9.0)
Range		0.0 - 14.0	2.0 - 12.0	2.0 - 15.0	4.0 - 12.0	0.0 - 15.0
Drug class category	290
Anti-androgens/hormone receptor antagonists		74 (71.8%)	24 (23.3%)	5 (4.85%)	0 (0%)	103 (100.0%)
Anti-neoplastic agents		146 (78.1%)	27 (14.4%)	11 (5.88%)	3 (1.60%)	187 (100.0%)
Diagnosis category	290
Breast		34 (82.9%)	4 (9.76%)	2 (4.88%)	1 (2.44%)	41 (100.0%)
Central nervous system		24 (80.0%)	4 (13.3%)	2 (6.67%)	0 (0%)	30 (100.0%)
GI		37 (78.7%)	6 (12.8%)	3 (6.38%)	1 (2.13%)	47 (100.0%)
GU		94 (73.4%)	28 (21.9%)	5 (3.91%)	1 (0.78%)	128 (100.0%)
GYN		3 (75.0%)	1 (25.0%)	0 (0%)	0 (0%)	4 (100.0%)
Head/neck		6 (85.7%)	1 (14.3%)	0 (0%)	0 (0%)	7 (100.0%)
Lung		13 (81.3%)	3 (18.8%)	0 (0%)	0 (0%)	16 (100.0%)
Melanoma/sarcoma		9 (52.9%)	4 (23.5%)	4 (23.5%)	0 (0%)	17 (100.0%)
What is the patient's cancer stage?	290
stage I		11 (100.0%)	0 (0%)	0 (0%)	0 (0%)	11 (100.0%)
stage II		26 (66.7%)	10 (25.6%)	3 (7.69%)	0 (0%)	39 (100.0%)
stage III		35 (76.1%)	9 (19.6%)	1 (2.17%)	1 (2.17%)	46 (100.0%)
stage IV		145 (76.7%)	30 (15.9%)	12 (6.35%)	2 (1.06%)	189 (100.0%)
staging not available		3 (60.0%)	2 (40.0%)	0 (0%)	0 (0%)	5 (100.0%)
¹ n (%)

Characteristic	N	OR¹	95% CI¹	p-value
Questionnaire response	290
Yes		—	—
No		0.37	0.21, 0.64	<0.001
Sex	290
Female		—	—
Male		0.92	0.53, 1.60	0.8
Age group	290
< 60		—	—
>= 60		1.34	0.74, 2.53	0.3
Charlson Comorbidity Index Score	290	1.00	0.91, 1.11	>0.9
Drug class category	290
Anti-androgens/hormone receptor antagonists		—	—
Anti-neoplastic agents		0.77	0.45, 1.33	0.3
Diagnosis category	290
Breast		—	—
Central nervous system		1.18	0.34, 3.99	0.8
GI		1.31	0.45, 3.98	0.6
GU		1.63	0.69, 4.31	0.3
GYN		1.43	0.07, 12.2	0.8
Head/neck		0.75	0.04, 5.33	0.8
Lung		1.02	0.20, 4.25	>0.9
Melanoma/sarcoma		4.63	1.36, 16.4	0.015
cancer_stage	290
stage II		—	—
stage I		-21.3
stage III		-0.45
stage IV		-0.45
staging not available		0.14
¹ OR = Odds Ratio, CI = Confidence Interval

label	levels	effect	conf.low	conf.high	d.f.	P
Questionnaire response	Yes vs. No	2.793	1.554	5.019	1	<0.001
Charlson index	9 vs. 5	1.059	0.668	1.677	1	0.808
Sex	Female vs. Male	1.466	0.719	2.991	1	0.293
Age group	< 60 vs. >= 60	0.774	0.376	1.591	1	0.485
Medication category	Anti-androgens/hormone receptor antagonists vs. Anti-neoplastic agents	1.189	0.559	2.528	1	0.653

Logistic (Proportional Odds) Ordinal Regression Model

orm(formula = n_ae_interventions_cat ~ questionnaire_response + 
    charlson + r_sex + r_age_group + med_recat, data = oa %>% 
    filter(per_protocol == "Yes"))

Frequencies of Responses

        0         1         2 3 or more 
      220        51        16         3

	Model Likelihood Ratio Test	Discrimination Indexes	Rank Discrim. Indexes
Obs 290	LR χ² 14.25	R² 0.063	ρ 0.204
Distinct Y 4	d.f. 5	R²_5,290 0.031
Y_0.5 1	Pr(>χ²) 0.0141	R²_5,161.8 0.056
max \|∂log L/∂β\| 0.0002	Score χ² 14.90	\|Pr(Y ≥ median)-½\| 0.258
	Pr(>χ²) 0.0108

	β	S.E.	Wald Z	Pr(>\|Z\|)
y≥1	-0.4167	0.5785	-0.72	0.4714
y≥2	-1.9878	0.6054	-3.28	0.0010
y≥3 or more	-3.9150	0.8043	-4.87	<0.0001
questionnaire_response=No	-1.0272	0.2990	-3.44	0.0006
charlson	0.0143	0.0586	0.24	0.8078
r_sex=Male	-0.3826	0.3638	-1.05	0.2930
r_age_group=≥ 60	0.2568	0.3681	0.70	0.4854
med_recat=Anti-neoplastic agents	-0.1732	0.3849	-0.45	0.6527

5 90-day outcomes

Clinical outcomes assessed within 90 days of treatment initiation included healthcare utilization (hospitalization or ED visit), treatment modifications (medication change or discontinuation), and dose modification (dose change or interruption)

5.1 Outcome summaries

Characteristic	N	Study assignment		p-value²	Overall, N = 387¹
Characteristic	N	Case, N = 182¹	Control, N = 205¹	p-value²	Overall, N = 387¹
Number of Dose interruptions related to AEs	387			0.064
0		177 (97.3%)	191 (93.2%)		368 (95.1%)
1		5 (2.75%)	14 (6.83%)		19 (4.91%)
Number of Dose changes related to AEs	387			0.631
0		169 (92.9%)	185 (90.2%)		354 (91.5%)
1		12 (6.59%)	17 (8.29%)		29 (7.49%)
2		1 (0.55%)	3 (1.46%)		4 (1.03%)
Number of Hospitalizations due to cancer	387			0.020
0		164 (90.1%)	164 (80.0%)		328 (84.8%)
1		13 (7.14%)	32 (15.6%)		45 (11.6%)
2		5 (2.75%)	9 (4.39%)		14 (3.62%)
Number of ED visits due to cancer	387			0.106
0		170 (93.4%)	181 (88.3%)		351 (90.7%)
1		8 (4.40%)	20 (9.76%)		28 (7.24%)
2		3 (1.65%)	4 (1.95%)		7 (1.81%)
4		1 (0.55%)	0 (0%)		1 (0.26%)
Discontunation related to AEs	387			0.766
0		165 (90.7%)	184 (89.8%)		349 (90.2%)
1		17 (9.34%)	21 (10.2%)		38 (9.82%)
Medication change related to AEs	387			0.306
0		172 (94.5%)	198 (96.6%)		370 (95.6%)
1		10 (5.49%)	6 (2.93%)		16 (4.13%)
2		0 (0%)	1 (0.49%)		1 (0.26%)
Number of Healthcare utilization instances	387			0.007
0		155 (85.2%)	151 (73.7%)		306 (79.1%)
1		20 (11.0%)	34 (16.6%)		54 (14.0%)
2		4 (2.20%)	16 (7.80%)		20 (5.17%)
3		1 (0.55%)	4 (1.95%)		5 (1.29%)
4		1 (0.55%)	0 (0%)		1 (0.26%)
6		1 (0.55%)	0 (0%)		1 (0.26%)
Number of Dose modifications	387			0.210
0		166 (91.2%)	177 (86.3%)		343 (88.6%)
1		13 (7.14%)	19 (9.27%)		32 (8.27%)
2		3 (1.65%)	9 (4.39%)		12 (3.10%)
Number of Treatment modifications	387			0.250
0		165 (90.7%)	184 (89.8%)		349 (90.2%)
1		7 (3.85%)	14 (6.83%)		21 (5.43%)
2		10 (5.49%)	6 (2.93%)		16 (4.13%)
3		0 (0%)	1 (0.49%)		1 (0.26%)
¹ n (%)
² Pearson’s Chi-squared test; Fisher’s exact test

Characteristic	Study assignment		p-value²	Overall, N = 387¹
Characteristic	Case, N = 182¹	Control, N = 205¹	p-value²	Overall, N = 387¹
Any dose interruptions related to AEs	5 (2.75%)	14 (6.83%)	0.064	19 (4.91%)
Any dose changes related to AEs	13 (7.14%)	20 (9.76%)	0.358	33 (8.53%)
Any hospitalizations due to cancer	18 (9.89%)	41 (20.0%)	0.006	59 (15.2%)
Any ED visits due to cancer	12 (6.59%)	24 (11.7%)	0.084	36 (9.30%)
Any discontunation related to AEs	17 (9.34%)	21 (10.2%)	0.766	38 (9.82%)
Any medication change related to AEs	10 (5.49%)	7 (3.41%)	0.319	17 (4.39%)
Any healthcare utilization	27 (14.8%)	54 (26.3%)	0.005	81 (20.9%)
Any dose modification	16 (8.79%)	28 (13.7%)	0.132	44 (11.4%)
Any treatment modification	17 (9.34%)	21 (10.2%)	0.766	38 (9.82%)
¹ n (%)
² Pearson’s Chi-squared test

Characteristic	N	Questionnaire response		p-value²	Overall, N = 387¹
Characteristic	N	Yes, N = 85¹	No, N = 302¹	p-value²	Overall, N = 387¹
Number of Dose interruptions related to AEs	387			0.269
0		83 (97.6%)	285 (94.4%)		368 (95.1%)
1		2 (2.35%)	17 (5.63%)		19 (4.91%)
Number of Dose changes related to AEs	387			0.490
0		80 (94.1%)	274 (90.7%)		354 (91.5%)
1		4 (4.71%)	25 (8.28%)		29 (7.49%)
2		1 (1.18%)	3 (0.99%)		4 (1.03%)
Number of Hospitalizations due to cancer	387			0.004
0		81 (95.3%)	247 (81.8%)		328 (84.8%)
1		4 (4.71%)	41 (13.6%)		45 (11.6%)
2		0 (0%)	14 (4.64%)		14 (3.62%)
Number of ED visits due to cancer	387			0.949
0		79 (92.9%)	272 (90.1%)		351 (90.7%)
1		5 (5.88%)	23 (7.62%)		28 (7.24%)
2		1 (1.18%)	6 (1.99%)		7 (1.81%)
4		0 (0%)	1 (0.33%)		1 (0.26%)
Discontunation related to AEs	387			0.167
0		80 (94.1%)	269 (89.1%)		349 (90.2%)
1		5 (5.88%)	33 (10.9%)		38 (9.82%)
Medication change related to AEs	387			>0.999
0		82 (96.5%)	288 (95.4%)		370 (95.6%)
1		3 (3.53%)	13 (4.30%)		16 (4.13%)
2		0 (0%)	1 (0.33%)		1 (0.26%)
Number of Healthcare utilization instances	387			0.193
0		75 (88.2%)	231 (76.5%)		306 (79.1%)
1		9 (10.6%)	45 (14.9%)		54 (14.0%)
2		1 (1.18%)	19 (6.29%)		20 (5.17%)
3		0 (0%)	5 (1.66%)		5 (1.29%)
4		0 (0%)	1 (0.33%)		1 (0.26%)
6		0 (0%)	1 (0.33%)		1 (0.26%)
Number of Dose modifications	387			0.556
0		78 (91.8%)	265 (87.7%)		343 (88.6%)
1		6 (7.06%)	26 (8.61%)		32 (8.27%)
2		1 (1.18%)	11 (3.64%)		12 (3.10%)
Number of Treatment modifications	387			0.538
0		80 (94.1%)	269 (89.1%)		349 (90.2%)
1		2 (2.35%)	19 (6.29%)		21 (5.43%)
2		3 (3.53%)	13 (4.30%)		16 (4.13%)
3		0 (0%)	1 (0.33%)		1 (0.26%)
¹ n (%)
² Fisher’s exact test; Pearson’s Chi-squared test

Characteristic	Questionnaire response		p-value²	Overall, N = 387¹
Characteristic	Yes, N = 85¹	No, N = 302¹	p-value²	Overall, N = 387¹
Any dose interruptions related to AEs	2 (2.35%)	17 (5.63%)	0.269	19 (4.91%)
Any dose changes related to AEs	5 (5.88%)	28 (9.27%)	0.323	33 (8.53%)
Any hospitalizations due to cancer	4 (4.71%)	55 (18.2%)	0.002	59 (15.2%)
Any ED visits due to cancer	6 (7.06%)	30 (9.93%)	0.420	36 (9.30%)
Any discontunation related to AEs	5 (5.88%)	33 (10.9%)	0.167	38 (9.82%)
Any medication change related to AEs	3 (3.53%)	14 (4.64%)	>0.999	17 (4.39%)
Any healthcare utilization	10 (11.8%)	71 (23.5%)	0.019	81 (20.9%)
Any dose modification	7 (8.24%)	37 (12.3%)	0.303	44 (11.4%)
Any treatment modification	5 (5.88%)	33 (10.9%)	0.167	38 (9.82%)
¹ n (%)
² Fisher’s exact test; Pearson’s Chi-squared test

Characteristic	N	Questionnaire response		p-value²	Overall, N = 290¹
Characteristic	N	Yes, N = 85¹	No, N = 205¹	p-value²	Overall, N = 290¹
Number of Dose interruptions related to AEs	290			0.164
0		83 (97.6%)	191 (93.2%)		274 (94.5%)
1		2 (2.35%)	14 (6.83%)		16 (5.52%)
Number of Dose changes related to AEs	290			0.670
0		80 (94.1%)	185 (90.2%)		265 (91.4%)
1		4 (4.71%)	17 (8.29%)		21 (7.24%)
2		1 (1.18%)	3 (1.46%)		4 (1.38%)
Number of Hospitalizations due to cancer	290			0.002
0		81 (95.3%)	164 (80.0%)		245 (84.5%)
1		4 (4.71%)	32 (15.6%)		36 (12.4%)
2		0 (0%)	9 (4.39%)		9 (3.10%)
Number of ED visits due to cancer	290			0.609
0		79 (92.9%)	181 (88.3%)		260 (89.7%)
1		5 (5.88%)	20 (9.76%)		25 (8.62%)
2		1 (1.18%)	4 (1.95%)		5 (1.72%)
Discontunation related to AEs	290			0.237
0		80 (94.1%)	184 (89.8%)		264 (91.0%)
1		5 (5.88%)	21 (10.2%)		26 (8.97%)
Medication change related to AEs	290			0.806
0		82 (96.5%)	198 (96.6%)		280 (96.6%)
1		3 (3.53%)	6 (2.93%)		9 (3.10%)
2		0 (0%)	1 (0.49%)		1 (0.34%)
Number of Healthcare utilization instances	290			0.025
0		75 (88.2%)	151 (73.7%)		226 (77.9%)
1		9 (10.6%)	34 (16.6%)		43 (14.8%)
2		1 (1.18%)	16 (7.80%)		17 (5.86%)
3		0 (0%)	4 (1.95%)		4 (1.38%)
Number of Dose modifications	290			0.380
0		78 (91.8%)	177 (86.3%)		255 (87.9%)
1		6 (7.06%)	19 (9.27%)		25 (8.62%)
2		1 (1.18%)	9 (4.39%)		10 (3.45%)
Number of Treatment modifications	290			0.438
0		80 (94.1%)	184 (89.8%)		264 (91.0%)
1		2 (2.35%)	14 (6.83%)		16 (5.52%)
2		3 (3.53%)	6 (2.93%)		9 (3.10%)
3		0 (0%)	1 (0.49%)		1 (0.34%)
¹ n (%)
² Fisher’s exact test; Pearson’s Chi-squared test

Characteristic	Questionnaire response		p-value²	Overall, N = 290¹
Characteristic	Yes, N = 85¹	No, N = 205¹	p-value²	Overall, N = 290¹
Any dose interruptions related to AEs	2 (2.35%)	14 (6.83%)	0.164	16 (5.52%)
Any dose changes related to AEs	5 (5.88%)	20 (9.76%)	0.285	25 (8.62%)
Any hospitalizations due to cancer	4 (4.71%)	41 (20.0%)	0.001	45 (15.5%)
Any ED visits due to cancer	6 (7.06%)	24 (11.7%)	0.237	30 (10.3%)
Any discontunation related to AEs	5 (5.88%)	21 (10.2%)	0.237	26 (8.97%)
Any medication change related to AEs	3 (3.53%)	7 (3.41%)	>0.999	10 (3.45%)
Any healthcare utilization	10 (11.8%)	54 (26.3%)	0.006	64 (22.1%)
Any dose modification	7 (8.24%)	28 (13.7%)	0.197	35 (12.1%)
Any treatment modification	5 (5.88%)	21 (10.2%)	0.237	26 (8.97%)
¹ n (%)
² Fisher’s exact test; Pearson’s Chi-squared test

Outcome	OR¹	95% CI¹	p-value
Number of Healthcare utilization instances
Case	—	—
Control	2.08	1.26, 3.50	0.005
Number of Dose modifications
Case	—	—
Control	1.67	0.88, 3.25	0.123
Number of Treatment modifications
Case	—	—
Control	1.08	0.55, 2.14	0.821
¹ OR = Odds Ratio, CI = Confidence Interval

Outcome	OR¹	95% CI¹	p-value
Any treatment modification
Case	—	—
Control	1.11	0.57, 2.20	0.766
¹ OR = Odds Ratio, CI = Confidence Interval

5.2 Discontinuation and dose change reasons

Characteristic	N = 89¹
No selections made across all observations	2 (2.25%)
Common side effect	34 (38.2%)
No response, disease progression	31 (34.8%)
Therapy completed	16 (18.0%)
Patient decision	3 (3.37%)
Patient deceased	2 (2.25%)
Financial limitations	1 (1.12%)
Major side effect	1 (1.12%)
Provider decision	1 (1.12%)
Number of selections made
0	2 (2.25%)
1	85 (95.5%)
2	2 (2.25%)
¹ n (%)

Characteristic	N	N = 89¹
Selection	89
Common side effect		34 (38.2%)
No response, disease progression		31 (34.8%)
Therapy completed		16 (18.0%)
Patient decision		3 (3.37%)
Patient deceased		2 (2.25%)
Financial limitations		1 (1.12%)
Major side effect		1 (1.12%)
Provider decision		1 (1.12%)
¹ n (%)

Characteristic	N = 58¹
No selections made across all observations	0 (0%)
Common side effect	34 (58.6%)
Standard dose titration	27 (46.6%)
Number of selections made
1	55 (94.8%)
2	3 (5.17%)
¹ n (%)

Characteristic	N	N = 61¹
Selection	61
Common side effect		34 (55.7%)
Standard dose titration		27 (44.3%)
¹ n (%)

5.3 Descriptive statistics stratified by outcome

Characteristic	N	Any treatment modification		p-value²	Overall, N = 387¹
Characteristic	N	No, N = 349¹	Yes, N = 38¹	p-value²	Overall, N = 387¹
Study assignment	387			0.766
Case		165 (47.3%)	17 (44.7%)		182 (47.0%)
Control		184 (52.7%)	21 (55.3%)		205 (53.0%)
Questionnaire response	387			0.167
Yes		80 (22.9%)	5 (13.2%)		85 (22.0%)
No		269 (77.1%)	33 (86.8%)		302 (78.0%)
Sex	387			0.067
Female		139 (39.8%)	21 (55.3%)		160 (41.3%)
Male		210 (60.2%)	17 (44.7%)		227 (58.7%)
Age group	387			0.304
< 60		111 (31.8%)	9 (23.7%)		120 (31.0%)
>= 60		238 (68.2%)	29 (76.3%)		267 (69.0%)
Charlson Comorbidity Index Score	387			0.022
Mean (SD)		7.0 (2.8)	8.0 (2.1)		7.1 (2.7)
Median (IQR)		7.0 (5.0 - 9.0)	8.0 (7.0 - 9.8)		7.0 (5.0 - 9.0)
Range		0.0 - 16.0	3.0 - 11.0		0.0 - 16.0
Number of AE interventions (categorized)	387			0.687
0		275 (78.8%)	33 (86.8%)		308 (79.6%)
1		54 (15.5%)	5 (13.2%)		59 (15.2%)
2		16 (4.58%)	0 (0%)		16 (4.13%)
3 or more		4 (1.15%)	0 (0%)		4 (1.03%)
Drug class category	387			0.091
Anti-androgens/hormone receptor antagonists		121 (34.7%)	8 (21.1%)		129 (33.3%)
Anti-neoplastic agents		228 (65.3%)	30 (78.9%)		258 (66.7%)
Diagnosis category	387			0.426
Breast		54 (15.5%)	8 (21.1%)		62 (16.0%)
Central nervous system		42 (12.0%)	2 (5.26%)		44 (11.4%)
GI		50 (14.3%)	8 (21.1%)		58 (15.0%)
GU		149 (42.7%)	15 (39.5%)		164 (42.4%)
GYN		4 (1.15%)	1 (2.63%)		5 (1.29%)
Head/neck		9 (2.58%)	0 (0%)		9 (2.33%)
Lung		16 (4.58%)	3 (7.89%)		19 (4.91%)
Melanoma/sarcoma		25 (7.16%)	1 (2.63%)		26 (6.72%)
What is the patient's cancer stage?	387			0.264
stage I		17 (4.87%)	0 (0%)		17 (4.39%)
stage II		47 (13.5%)	2 (5.26%)		49 (12.7%)
stage III		60 (17.2%)	6 (15.8%)		66 (17.1%)
stage IV		220 (63.0%)	29 (76.3%)		249 (64.3%)
staging not available		5 (1.43%)	1 (2.63%)		6 (1.55%)
¹ n (%)
² Pearson’s Chi-squared test; Wilcoxon rank sum test; Fisher’s exact test

Characteristic	N	Any healthcare utilization		p-value²	Overall, N = 387¹
Characteristic	N	No, N = 306¹	Yes, N = 81¹	p-value²	Overall, N = 387¹
Study assignment	387			0.005
Case		155 (50.7%)	27 (33.3%)		182 (47.0%)
Control		151 (49.3%)	54 (66.7%)		205 (53.0%)
Questionnaire response	387			0.019
Yes		75 (24.5%)	10 (12.3%)		85 (22.0%)
No		231 (75.5%)	71 (87.7%)		302 (78.0%)
Sex	387			<0.001
Female		109 (35.6%)	51 (63.0%)		160 (41.3%)
Male		197 (64.4%)	30 (37.0%)		227 (58.7%)
Age group	387			0.033
< 60		87 (28.4%)	33 (40.7%)		120 (31.0%)
>= 60		219 (71.6%)	48 (59.3%)		267 (69.0%)
Charlson Comorbidity Index Score	387			0.328
Mean (SD)		7.0 (2.8)	7.3 (2.7)		7.1 (2.7)
Median (IQR)		7.0 (5.0 - 9.0)	7.0 (6.0 - 9.0)		7.0 (5.0 - 9.0)
Range		0.0 - 16.0	0.0 - 15.0		0.0 - 16.0
Number of AE interventions (categorized)	387			0.017
0		239 (78.1%)	69 (85.2%)		308 (79.6%)
1		52 (17.0%)	7 (8.64%)		59 (15.2%)
2		14 (4.58%)	2 (2.47%)		16 (4.13%)
3 or more		1 (0.33%)	3 (3.70%)		4 (1.03%)
Drug class category	387			<0.001
Anti-androgens/hormone receptor antagonists		122 (39.9%)	7 (8.64%)		129 (33.3%)
Anti-neoplastic agents		184 (60.1%)	74 (91.4%)		258 (66.7%)
Diagnosis category	387
Breast		50 (16.3%)	12 (14.8%)		62 (16.0%)
Central nervous system		29 (9.48%)	15 (18.5%)		44 (11.4%)
GI		36 (11.8%)	22 (27.2%)		58 (15.0%)
GU		143 (46.7%)	21 (25.9%)		164 (42.4%)
GYN		2 (0.65%)	3 (3.70%)		5 (1.29%)
Head/neck		8 (2.61%)	1 (1.23%)		9 (2.33%)
Lung		16 (5.23%)	3 (3.70%)		19 (4.91%)
Melanoma/sarcoma		22 (7.19%)	4 (4.94%)		26 (6.72%)
What is the patient's cancer stage?	387			0.023
stage I		15 (4.90%)	2 (2.47%)		17 (4.39%)
stage II		45 (14.7%)	4 (4.94%)		49 (12.7%)
stage III		56 (18.3%)	10 (12.3%)		66 (17.1%)
stage IV		186 (60.8%)	63 (77.8%)		249 (64.3%)
staging not available		4 (1.31%)	2 (2.47%)		6 (1.55%)
¹ n (%)
² Pearson’s Chi-squared test; Wilcoxon rank sum test; Fisher’s exact test

Characteristic	N	Any dose modification		p-value²	Overall, N = 387¹
Characteristic	N	No, N = 343¹	Yes, N = 44¹	p-value²	Overall, N = 387¹
Study assignment	387			0.132
Case		166 (48.4%)	16 (36.4%)		182 (47.0%)
Control		177 (51.6%)	28 (63.6%)		205 (53.0%)
Questionnaire response	387			0.303
Yes		78 (22.7%)	7 (15.9%)		85 (22.0%)
No		265 (77.3%)	37 (84.1%)		302 (78.0%)
Sex	387			0.361
Female		139 (40.5%)	21 (47.7%)		160 (41.3%)
Male		204 (59.5%)	23 (52.3%)		227 (58.7%)
Age group	387			0.360
< 60		109 (31.8%)	11 (25.0%)		120 (31.0%)
>= 60		234 (68.2%)	33 (75.0%)		267 (69.0%)
Charlson Comorbidity Index Score	387			0.004
Mean (SD)		6.9 (2.7)	8.2 (2.6)		7.1 (2.7)
Median (IQR)		7.0 (5.0 - 9.0)	9.0 (7.0 - 10.0)		7.0 (5.0 - 9.0)
Range		0.0 - 15.0	2.0 - 16.0		0.0 - 16.0
Number of AE interventions (categorized)	387			0.030
0		276 (80.5%)	32 (72.7%)		308 (79.6%)
1		49 (14.3%)	10 (22.7%)		59 (15.2%)
2		16 (4.66%)	0 (0%)		16 (4.13%)
3 or more		2 (0.58%)	2 (4.55%)		4 (1.03%)
Drug class category	387			<0.001
Anti-androgens/hormone receptor antagonists		127 (37.0%)	2 (4.55%)		129 (33.3%)
Anti-neoplastic agents		216 (63.0%)	42 (95.5%)		258 (66.7%)
Diagnosis category	387			0.419
Breast		53 (15.5%)	9 (20.5%)		62 (16.0%)
Central nervous system		42 (12.2%)	2 (4.55%)		44 (11.4%)
GI		50 (14.6%)	8 (18.2%)		58 (15.0%)
GU		148 (43.1%)	16 (36.4%)		164 (42.4%)
GYN		4 (1.17%)	1 (2.27%)		5 (1.29%)
Head/neck		8 (2.33%)	1 (2.27%)		9 (2.33%)
Lung		15 (4.37%)	4 (9.09%)		19 (4.91%)
Melanoma/sarcoma		23 (6.71%)	3 (6.82%)		26 (6.72%)
What is the patient's cancer stage?	387			0.039
stage I		16 (4.66%)	1 (2.27%)		17 (4.39%)
stage II		47 (13.7%)	2 (4.55%)		49 (12.7%)
stage III		63 (18.4%)	3 (6.82%)		66 (17.1%)
stage IV		212 (61.8%)	37 (84.1%)		249 (64.3%)
staging not available		5 (1.46%)	1 (2.27%)		6 (1.55%)
¹ n (%)
² Pearson’s Chi-squared test; Wilcoxon rank sum test; Fisher’s exact test

Characteristic	N	Any treatment modification		p-value²	Overall, N = 290¹
Characteristic	N	No, N = 264¹	Yes, N = 26¹	p-value²	Overall, N = 290¹
Study assignment	290			0.237
Case		80 (30.3%)	5 (19.2%)		85 (29.3%)
Control		184 (69.7%)	21 (80.8%)		205 (70.7%)
Questionnaire response	290			0.237
Yes		80 (30.3%)	5 (19.2%)		85 (29.3%)
No		184 (69.7%)	21 (80.8%)		205 (70.7%)
Sex	290			0.478
Female		103 (39.0%)	12 (46.2%)		115 (39.7%)
Male		161 (61.0%)	14 (53.8%)		175 (60.3%)
Age group	290			0.237
< 60		80 (30.3%)	5 (19.2%)		85 (29.3%)
>= 60		184 (69.7%)	21 (80.8%)		205 (70.7%)
Charlson Comorbidity Index Score	290			0.028
Mean (SD)		7.0 (2.7)	8.2 (2.2)		7.1 (2.7)
Median (IQR)		7.0 (5.0 - 9.0)	8.0 (7.0 - 10.0)		7.0 (5.0 - 9.0)
Range		0.0 - 15.0	3.0 - 11.0		0.0 - 15.0
Number of AE interventions (categorized)	290			0.689
0		199 (75.4%)	21 (80.8%)		220 (75.9%)
1		46 (17.4%)	5 (19.2%)		51 (17.6%)
2		16 (6.06%)	0 (0%)		16 (5.52%)
3 or more		3 (1.14%)	0 (0%)		3 (1.03%)
Drug class category	290			0.165
Anti-androgens/hormone receptor antagonists		97 (36.7%)	6 (23.1%)		103 (35.5%)
Anti-neoplastic agents		167 (63.3%)	20 (76.9%)		187 (64.5%)
Diagnosis category	290			0.414
Breast		37 (14.0%)	4 (15.4%)		41 (14.1%)
Central nervous system		30 (11.4%)	0 (0%)		30 (10.3%)
GI		41 (15.5%)	6 (23.1%)		47 (16.2%)
GU		115 (43.6%)	13 (50.0%)		128 (44.1%)
GYN		3 (1.14%)	1 (3.85%)		4 (1.38%)
Head/neck		7 (2.65%)	0 (0%)		7 (2.41%)
Lung		15 (5.68%)	1 (3.85%)		16 (5.52%)
Melanoma/sarcoma		16 (6.06%)	1 (3.85%)		17 (5.86%)
What is the patient's cancer stage?	290			0.331
stage I		11 (4.17%)	0 (0%)		11 (3.79%)
stage II		38 (14.4%)	1 (3.85%)		39 (13.4%)
stage III		41 (15.5%)	5 (19.2%)		46 (15.9%)
stage IV		170 (64.4%)	19 (73.1%)		189 (65.2%)
staging not available		4 (1.52%)	1 (3.85%)		5 (1.72%)
¹ n (%)
² Pearson’s Chi-squared test; Wilcoxon rank sum test; Fisher’s exact test

Characteristic	N	Any healthcare utilization		p-value²	Overall, N = 290¹
Characteristic	N	No, N = 226¹	Yes, N = 64¹	p-value²	Overall, N = 290¹
Study assignment	290			0.006
Case		75 (33.2%)	10 (15.6%)		85 (29.3%)
Control		151 (66.8%)	54 (84.4%)		205 (70.7%)
Questionnaire response	290			0.006
Yes		75 (33.2%)	10 (15.6%)		85 (29.3%)
No		151 (66.8%)	54 (84.4%)		205 (70.7%)
Sex	290			<0.001
Female		74 (32.7%)	41 (64.1%)		115 (39.7%)
Male		152 (67.3%)	23 (35.9%)		175 (60.3%)
Age group	290			0.187
< 60		62 (27.4%)	23 (35.9%)		85 (29.3%)
>= 60		164 (72.6%)	41 (64.1%)		205 (70.7%)
Charlson Comorbidity Index Score	290			0.422
Mean (SD)		7.1 (2.7)	7.4 (2.8)		7.1 (2.7)
Median (IQR)		7.0 (5.0 - 9.0)	7.5 (6.0 - 9.3)		7.0 (5.0 - 9.0)
Range		0.0 - 14.0	0.0 - 15.0		0.0 - 15.0
Number of AE interventions (categorized)	290			0.079
0		167 (73.9%)	53 (82.8%)		220 (75.9%)
1		44 (19.5%)	7 (10.9%)		51 (17.6%)
2		14 (6.19%)	2 (3.13%)		16 (5.52%)
3 or more		1 (0.44%)	2 (3.13%)		3 (1.03%)
Drug class category	290			<0.001
Anti-androgens/hormone receptor antagonists		97 (42.9%)	6 (9.38%)		103 (35.5%)
Anti-neoplastic agents		129 (57.1%)	58 (90.6%)		187 (64.5%)
Diagnosis category	290
Breast		30 (13.3%)	11 (17.2%)		41 (14.1%)
Central nervous system		21 (9.29%)	9 (14.1%)		30 (10.3%)
GI		28 (12.4%)	19 (29.7%)		47 (16.2%)
GU		112 (49.6%)	16 (25.0%)		128 (44.1%)
GYN		1 (0.44%)	3 (4.69%)		4 (1.38%)
Head/neck		7 (3.10%)	0 (0%)		7 (2.41%)
Lung		13 (5.75%)	3 (4.69%)		16 (5.52%)
Melanoma/sarcoma		14 (6.19%)	3 (4.69%)		17 (5.86%)
What is the patient's cancer stage?	290			0.084
stage I		9 (3.98%)	2 (3.13%)		11 (3.79%)
stage II		36 (15.9%)	3 (4.69%)		39 (13.4%)
stage III		37 (16.4%)	9 (14.1%)		46 (15.9%)
stage IV		141 (62.4%)	48 (75.0%)		189 (65.2%)
staging not available		3 (1.33%)	2 (3.13%)		5 (1.72%)
¹ n (%)
² Pearson’s Chi-squared test; Wilcoxon rank sum test; Fisher’s exact test

Characteristic	N	Any dose modification		p-value²	Overall, N = 290¹
Characteristic	N	No, N = 255¹	Yes, N = 35¹	p-value²	Overall, N = 290¹
Study assignment	290			0.197
Case		78 (30.6%)	7 (20.0%)		85 (29.3%)
Control		177 (69.4%)	28 (80.0%)		205 (70.7%)
Questionnaire response	290			0.197
Yes		78 (30.6%)	7 (20.0%)		85 (29.3%)
No		177 (69.4%)	28 (80.0%)		205 (70.7%)
Sex	290			0.250
Female		98 (38.4%)	17 (48.6%)		115 (39.7%)
Male		157 (61.6%)	18 (51.4%)		175 (60.3%)
Age group	290			0.371
< 60		77 (30.2%)	8 (22.9%)		85 (29.3%)
>= 60		178 (69.8%)	27 (77.1%)		205 (70.7%)
Charlson Comorbidity Index Score	290			0.032
Mean (SD)		7.0 (2.7)	7.9 (2.5)		7.1 (2.7)
Median (IQR)		7.0 (5.0 - 9.0)	9.0 (7.0 - 10.0)		7.0 (5.0 - 9.0)
Range		0.0 - 15.0	2.0 - 12.0		0.0 - 15.0
Number of AE interventions (categorized)	290			0.010
0		197 (77.3%)	23 (65.7%)		220 (75.9%)
1		41 (16.1%)	10 (28.6%)		51 (17.6%)
2		16 (6.27%)	0 (0%)		16 (5.52%)
3 or more		1 (0.39%)	2 (5.71%)		3 (1.03%)
Drug class category	290			<0.001
Anti-androgens/hormone receptor antagonists		101 (39.6%)	2 (5.71%)		103 (35.5%)
Anti-neoplastic agents		154 (60.4%)	33 (94.3%)		187 (64.5%)
Diagnosis category	290			0.781
Breast		35 (13.7%)	6 (17.1%)		41 (14.1%)
Central nervous system		28 (11.0%)	2 (5.71%)		30 (10.3%)
GI		41 (16.1%)	6 (17.1%)		47 (16.2%)
GU		114 (44.7%)	14 (40.0%)		128 (44.1%)
GYN		3 (1.18%)	1 (2.86%)		4 (1.38%)
Head/neck		6 (2.35%)	1 (2.86%)		7 (2.41%)
Lung		13 (5.10%)	3 (8.57%)		16 (5.52%)
Melanoma/sarcoma		15 (5.88%)	2 (5.71%)		17 (5.86%)
What is the patient's cancer stage?	290			0.145
stage I		11 (4.31%)	0 (0%)		11 (3.79%)
stage II		37 (14.5%)	2 (5.71%)		39 (13.4%)
stage III		43 (16.9%)	3 (8.57%)		46 (15.9%)
stage IV		160 (62.7%)	29 (82.9%)		189 (65.2%)
staging not available		4 (1.57%)	1 (2.86%)		5 (1.72%)
¹ n (%)
² Pearson’s Chi-squared test; Wilcoxon rank sum test; Fisher’s exact test

5.4 Univariate analyses

ITT is the entire cohort, comparing those randomized to treatment vs those randomized to usual care

mITT is the entire cohort, comparing those who responded vs those who did not

Per protocol is case responders and all controls, comparing those who responded vs those who did not

Characteristic	Treatment modification			Healthcare utilization			Dose modification
Characteristic	OR¹	95% CI¹	p-value	OR¹	95% CI¹	p-value	OR¹	95% CI¹	p-value
Questionnaire response: Yes	0.51	0.17, 1.24	0.174	0.43	0.20, 0.85	0.021	0.64	0.25, 1.42	0.306
Study assignment: Control	1.11	0.57, 2.20	0.766	2.05	1.24, 3.47	0.006	1.64	0.87, 3.21	0.135
Sex: Male	0.54	0.27, 1.05	0.070	0.33	0.19, 0.54	0	0.75	0.40, 1.41	0.362
Age group: >= 60	1.50	0.71, 3.47	0.307	0.58	0.35, 0.97	0.034	1.40	0.70, 2.99	0.362
Charlson Comorbidity Index Score	1.15	1.02, 1.31	0.029	1.05	0.96, 1.15	0.334	1.20	1.06, 1.36	0.004
Drug class category: Anti-neoplastic agents	1.99	0.93, 4.78	0.096	7.01	3.34, 17.2	0	12.3	3.72, 76.5	0.001
¹ OR = Odds Ratio, CI = Confidence Interval

Characteristic	Treatment modification			Healthcare utilization			Dose modification
Characteristic	OR¹	95% CI¹	p-value	OR¹	95% CI¹	p-value	OR¹	95% CI¹	p-value
Questionnaire response: Yes	0.55	0.18, 1.40	0.243	0.37	0.17, 0.74	0.008	0.57	0.22, 1.29	0.202
Study assignment: Control	1.83	0.71, 5.62	0.243	2.68	1.34, 5.86	0.008	1.76	0.78, 4.54	0.202
Sex: Male	0.75	0.33, 1.70	0.479	0.27	0.15, 0.48	0	0.66	0.32, 1.35	0.252
Age group: >= 60	1.83	0.71, 5.62	0.243	0.67	0.38, 1.23	0.189	1.46	0.66, 3.57	0.373
Charlson Comorbidity Index Score	1.18	1.01, 1.39	0.037	1.04	0.94, 1.16	0.407	1.14	1.00, 1.31	0.059
Drug class category: Anti-neoplastic agents	1.94	0.79, 5.44	0.171	7.27	3.24, 19.5	0	10.8	3.19, 67.6	0.001
¹ OR = Odds Ratio, CI = Confidence Interval

Characteristic	Healthcare utilization			Dose modification
Characteristic	OR¹	95% CI¹	p-value	OR¹	95% CI¹	p-value
Questionnaire response: Yes	0.42	0.19, 0.82	0.016	0.63	0.25, 1.40	0.290
Study assignment: Control	2.08	1.26, 3.50	0.005	1.67	0.88, 3.25	0.123
Sex: Male	0.35	0.21, 0.57	0	0.76	0.41, 1.44	0.398
Age group: >= 60	0.59	0.36, 0.98	0.040	1.40	0.70, 2.99	0.362
Charlson Comorbidity Index Score	1.04	0.95, 1.13	0.437	1.19	1.06, 1.35	0.004
Drug class category: Anti-neoplastic agents	7.11	3.38, 17.4	0	12.3	3.69, 76.0	0.001
¹ OR = Odds Ratio, CI = Confidence Interval

Characteristic	Healthcare utilization			Dose modification
Characteristic	OR¹	95% CI¹	p-value	OR¹	95% CI¹	p-value
Questionnaire response: Yes	0.36	0.16, 0.71	0.006	0.56	0.22, 1.26	0.188
Study assignment: Control	2.79	1.40, 6.08	0.006	1.79	0.79, 4.61	0.188
Sex: Male	0.29	0.16, 0.51	0	0.67	0.33, 1.37	0.270
Age group: >= 60	0.69	0.39, 1.25	0.209	1.47	0.66, 3.58	0.367
Charlson Comorbidity Index Score	1.04	0.94, 1.15	0.504	1.14	1.00, 1.32	0.054
Drug class category: Anti-neoplastic agents	7.36	3.29, 19.7	0	10.7	3.17, 67.1	0.001
¹ OR = Odds Ratio, CI = Confidence Interval

Characteristic	ITT & mITT - logistic			Per protocol - logistic
Characteristic	OR¹	95% CI¹	p-value	OR¹	95% CI¹	p-value
Questionnaire response: Yes	0.51	0.17, 1.24	0.174	0.55	0.18, 1.40	0.243
Study assignment: Control	1.11	0.57, 2.20	0.766	1.83	0.71, 5.62	0.243
Sex: Male	0.54	0.27, 1.05	0.070	0.75	0.33, 1.70	0.479
Age group: >= 60	1.50	0.71, 3.47	0.307	1.83	0.71, 5.62	0.243
Charlson Comorbidity Index Score	1.15	1.02, 1.31	0.029	1.18	1.01, 1.39	0.037
Drug class category: Anti-neoplastic agents	1.99	0.93, 4.78	0.096	1.94	0.79, 5.44	0.171
¹ OR = Odds Ratio, CI = Confidence Interval

Characteristic	ITT & mITT - logistic			Per protocol - logistic			ITT & mITT - ordinal			Per protocol - ordinal
Characteristic	OR¹	95% CI¹	p-value	OR¹	95% CI¹	p-value	OR¹	95% CI¹	p-value	OR¹	95% CI¹	p-value
Questionnaire response: Yes	0.43	0.20, 0.85	0.021	0.37	0.17, 0.74	0.008	0.42	0.19, 0.82	0.016	0.36	0.16, 0.71	0.006
Study assignment: Control	2.05	1.24, 3.47	0.006	2.68	1.34, 5.86	0.008	2.08	1.26, 3.50	0.005	2.79	1.40, 6.08	0.006
Sex: Male	0.33	0.19, 0.54	0	0.27	0.15, 0.48	0	0.35	0.21, 0.57	0	0.29	0.16, 0.51	0
Age group: >= 60	0.58	0.35, 0.97	0.034	0.67	0.38, 1.23	0.189	0.59	0.36, 0.98	0.040	0.69	0.39, 1.25	0.209
Charlson Comorbidity Index Score	1.05	0.96, 1.15	0.334	1.04	0.94, 1.16	0.407	1.04	0.95, 1.13	0.437	1.04	0.94, 1.15	0.504
Drug class category: Anti-neoplastic agents	7.01	3.34, 17.2	0	7.27	3.24, 19.5	0	7.11	3.38, 17.4	0	7.36	3.29, 19.7	0
¹ OR = Odds Ratio, CI = Confidence Interval

Characteristic	ITT & mITT - logistic			Per protocol - logistic			ITT & mITT - ordinal			Per protocol - ordinal
Characteristic	OR¹	95% CI¹	p-value	OR¹	95% CI¹	p-value	OR¹	95% CI¹	p-value	OR¹	95% CI¹	p-value
Questionnaire response: Yes	0.64	0.25, 1.42	0.306	0.57	0.22, 1.29	0.202	0.63	0.25, 1.40	0.290	0.56	0.22, 1.26	0.188
Study assignment: Control	1.64	0.87, 3.21	0.135	1.76	0.78, 4.54	0.202	1.67	0.88, 3.25	0.123	1.79	0.79, 4.61	0.188
Sex: Male	0.75	0.40, 1.41	0.362	0.66	0.32, 1.35	0.252	0.76	0.41, 1.44	0.398	0.67	0.33, 1.37	0.270
Age group: >= 60	1.40	0.70, 2.99	0.362	1.46	0.66, 3.57	0.373	1.40	0.70, 2.99	0.362	1.47	0.66, 3.58	0.367
Charlson Comorbidity Index Score	1.20	1.06, 1.36	0.004	1.14	1.00, 1.31	0.059	1.19	1.06, 1.35	0.004	1.14	1.00, 1.32	0.054
Drug class category: Anti-neoplastic agents	12.3	3.72, 76.5	0.001	10.8	3.19, 67.6	0.001	12.3	3.69, 76.0	0.001	10.7	3.17, 67.1	0.001
¹ OR = Odds Ratio, CI = Confidence Interval

5.5 Multivariable models of composite outcomes

5.5.1 Models

label	levels	effect	conf.low	conf.high	d.f.	P
Questionnaire response	Yes vs. No	0.503	0.243	1.040	1	0.064
Charlson index	9 vs. 5	1.639	1.056	2.544	1	0.028
Sex	Female vs. Male	2.802	1.656	4.743	1	<0.001
Age group	< 60 vs. >= 60	1.979	1.085	3.609	1	0.026

Logistic (Proportional Odds) Ordinal Regression Model

orm(formula = as.formula(paste0(VAR, covs)), data = DAT %>% mutate(outcome_trt_mod_binary = outcome_trt_mod_binary == 
    "Yes"))

Frequencies of Responses

  0   1   2   3   4   6 
306  54  20   5   1   1

	Model Likelihood Ratio Test	Discrimination Indexes	Rank Discrim. Indexes
Obs 387	LR χ² 29.02	R² 0.096	ρ 0.268
Distinct Y 6	d.f. 4	R²_4,387 0.063
Y_0.5 0	Pr(>χ²) <0.0001	R²_4,194.6 0.121
max \|∂log L/∂β\| 2×10^-6	Score χ² 27.78	\|Pr(Y ≥ median)-½\| 0.293
	Pr(>χ²) <0.0001

	β	S.E.	Wald Z	Pr(>\|Z\|)
y≥1	-1.8250	0.4787	-3.81	0.0001
y≥2	-3.1541	0.5058	-6.24	<0.0001
y≥3	-4.5697	0.6022	-7.59	<0.0001
y≥4	-5.8337	0.8485	-6.88	<0.0001
y≥6	-6.5288	1.1046	-5.91	<0.0001
r_sex=Male	-1.0304	0.2684	-3.84	0.0001
r_age_group=≥ 60	-0.6823	0.3067	-2.22	0.0261
charlson	0.1235	0.0561	2.20	0.0277
questionnaire_response=No	0.6879	0.3709	1.85	0.0636

label	levels	effect	conf.low	conf.high	d.f.	P
Questionnaire response	Yes vs. No	0.737	0.311	1.747	1	0.488
Charlson index	9 vs. 5	2.221	1.269	3.888	1	0.005
Sex	Female vs. Male	1.524	0.789	2.945	1	0.209
Age group	< 60 vs. >= 60	1.133	0.498	2.578	1	0.766

Logistic (Proportional Odds) Ordinal Regression Model

orm(formula = as.formula(paste0(VAR, covs)), data = DAT %>% mutate(outcome_trt_mod_binary = outcome_trt_mod_binary == 
    "Yes"))

	Model Likelihood Ratio Test	Discrimination Indexes	Rank Discrim. Indexes
Obs 387	LR χ² 11.24	R² 0.050	ρ 0.178
0 343	d.f. 4	R²_4,387 0.019
1 32	Pr(>χ²) 0.0240	R²_4,117.3 0.060
2 12	Score χ² 10.77	\|Pr(Y ≥ median)-½\| 0.386
Distinct Y 3	Pr(>χ²) 0.0293
Y_0.5 0
max \|∂log L/∂β\| 0.003

	β	S.E.	Wald Z	Pr(>\|Z\|)
y≥1	-3.4882	0.6363	-5.48	<0.0001
y≥2	-4.9015	0.6887	-7.12	<0.0001
r_sex=Male	-0.4216	0.3360	-1.25	0.2095
r_age_group=≥ 60	-0.1250	0.4194	-0.30	0.7656
charlson	0.1995	0.0714	2.79	0.0052
questionnaire_response=No	0.3050	0.4403	0.69	0.4885

label	levels	effect	conf.low	conf.high	d.f.	P
Questionnaire response	Yes vs. No	0.608	0.226	1.637	1	0.325
Charlson index	9 vs. 5	1.858	1.019	3.388	1	0.043
Sex	Female vs. Male	2.122	1.050	4.288	1	0.036
Age group	< 60 vs. >= 60	0.873	0.359	2.126	1	0.765

Logistic (Proportional Odds) Ordinal Regression Model

orm(formula = as.formula(paste0(VAR, covs)), data = DAT %>% mutate(outcome_trt_mod_binary = outcome_trt_mod_binary == 
    "Yes"))

	Model Likelihood Ratio Test	Discrimination Indexes	Rank Discrim. Indexes
Obs 387	LR χ² 11.06	R² 0.059	ρ 0.169
FALSE 349	d.f. 4	R²_4,387 0.018
TRUE 38	Pr(>χ²) 0.0259	R²_4,102.8 0.066
Distinct Y 2	Score χ² 10.51	\|Pr(Y ≥ median)-½\| 0.402
Y_0.5 1	Pr(>χ²) 0.0326
max \|∂log L/∂β\| 0.007

	β	S.E.	Wald Z	Pr(>\|Z\|)
Intercept	-3.4923	0.6977	-5.01	<0.0001
r_sex=Male	-0.7523	0.3590	-2.10	0.0361
r_age_group=≥ 60	0.1356	0.4539	0.30	0.7652
charlson	0.1548	0.0767	2.02	0.0434
questionnaire_response=No	0.4971	0.5050	0.98	0.3249

label	levels	effect	conf.low	conf.high	d.f.	P
Questionnaire response	Yes vs. No	0.425	0.201	0.899	1	0.025
Charlson index	9 vs. 5	1.501	0.905	2.490	1	0.116
Sex	Female vs. Male	3.407	1.865	6.224	1	<0.001
Age group	< 60 vs. >= 60	1.541	0.768	3.090	1	0.223

Logistic (Proportional Odds) Ordinal Regression Model

orm(formula = as.formula(paste0(VAR, covs)), data = DAT %>% mutate(outcome_trt_mod_binary = outcome_trt_mod_binary == 
    "Yes"))

Frequencies of Responses

  0   1   2   3 
226  43  17   4

	Model Likelihood Ratio Test	Discrimination Indexes	Rank Discrim. Indexes
Obs 290	LR χ² 28.25	R² 0.123	ρ 0.290
Distinct Y 4	d.f. 4	R²_4,290 0.080
Y_0.5 0	Pr(>χ²) <0.0001	R²_4,151.7 0.148
max \|∂log L/∂β\| 4×10^-6	Score χ² 27.04	\|Pr(Y ≥ median)-½\| 0.281
	Pr(>χ²) <0.0001

	β	S.E.	Wald Z	Pr(>\|Z\|)
y≥1	-1.7295	0.5148	-3.36	0.0008
y≥2	-3.1087	0.5480	-5.67	<0.0001
y≥3	-4.8551	0.7106	-6.83	<0.0001
r_sex=Male	-1.2259	0.3074	-3.99	<0.0001
r_age_group=≥ 60	-0.4323	0.3550	-1.22	0.2233
charlson	0.1015	0.0646	1.57	0.1161
questionnaire_response=No	0.8546	0.3819	2.24	0.0252

label	levels	effect	conf.low	conf.high	d.f.	P
Questionnaire response	Yes vs. No	0.638	0.263	1.547	1	0.320
Charlson index	9 vs. 5	1.714	0.916	3.207	1	0.092
Sex	Female vs. Male	1.639	0.785	3.419	1	0.188
Age group	< 60 vs. >= 60	0.875	0.344	2.228	1	0.779

Logistic (Proportional Odds) Ordinal Regression Model

orm(formula = as.formula(paste0(VAR, covs)), data = DAT %>% mutate(outcome_trt_mod_binary = outcome_trt_mod_binary == 
    "Yes"))

	Model Likelihood Ratio Test	Discrimination Indexes	Rank Discrim. Indexes
Obs 290	LR χ² 7.02	R² 0.041	ρ 0.165
0 255	d.f. 4	R²_4,290 0.010
1 25	Pr(>χ²) 0.1350	R²_4,92.6 0.032
2 10	Score χ² 6.72	\|Pr(Y ≥ median)-½\| 0.379
Distinct Y 3	Pr(>χ²) 0.1513
Y_0.5 0
max \|∂log L/∂β\| 0.001

	β	S.E.	Wald Z	Pr(>\|Z\|)
y≥1	-3.1496	0.6813	-4.62	<0.0001
y≥2	-4.5166	0.7374	-6.12	<0.0001
r_sex=Male	-0.4938	0.3753	-1.32	0.1882
r_age_group=≥ 60	0.1336	0.4770	0.28	0.7794
charlson	0.1347	0.0799	1.69	0.0920
questionnaire_response=No	0.4488	0.4515	0.99	0.3203

label	levels	effect	conf.low	conf.high	d.f.	P
Questionnaire response	Yes vs. No	0.635	0.227	1.780	1	0.388
Charlson index	9 vs. 5	1.873	0.906	3.871	1	0.090
Sex	Female vs. Male	1.527	0.657	3.549	1	0.325
Age group	< 60 vs. >= 60	0.755	0.245	2.326	1	0.625

Logistic (Proportional Odds) Ordinal Regression Model

orm(formula = as.formula(paste0(VAR, covs)), data = DAT %>% mutate(outcome_trt_mod_binary = outcome_trt_mod_binary == 
    "Yes"))

	Model Likelihood Ratio Test	Discrimination Indexes	Rank Discrim. Indexes
Obs 290	LR χ² 6.71	R² 0.050	ρ 0.152
FALSE 264	d.f. 4	R²_4,290 0.009
TRUE 26	Pr(>χ²) 0.1521	R²_4,71 0.037
Distinct Y 2	Score χ² 6.31	\|Pr(Y ≥ median)-½\| 0.410
Y_0.5 1	Pr(>χ²) 0.1769
max \|∂log L/∂β\| 0.003

	β	S.E.	Wald Z	Pr(>\|Z\|)
Intercept	-3.8261	0.8165	-4.69	<0.0001
r_sex=Male	-0.4235	0.4302	-0.98	0.3249
r_age_group=≥ 60	0.2810	0.5741	0.49	0.6246
charlson	0.1569	0.0926	1.69	0.0902
questionnaire_response=No	0.4534	0.5257	0.86	0.3884

label	levels	effect	conf.low	conf.high	d.f.	P
Treatment assignment	Case vs. Control	0.498	0.294	0.842	1	0.009
Charlson index	9 vs. 5	1.638	1.053	2.549	1	0.029
Sex	Female vs. Male	2.903	1.714	4.916	1	<0.001
Age group	< 60 vs. >= 60	2.046	1.119	3.743	1	0.020

Logistic (Proportional Odds) Ordinal Regression Model

orm(formula = as.formula(paste0(VAR, covs)), data = DAT %>% mutate(outcome_trt_mod_binary = outcome_trt_mod_binary == 
    "Yes"))

Frequencies of Responses

  0   1   2   3   4   6 
306  54  20   5   1   1

	Model Likelihood Ratio Test	Discrimination Indexes	Rank Discrim. Indexes
Obs 387	LR χ² 32.20	R² 0.106	ρ 0.282
Distinct Y 6	d.f. 4	R²_4,387 0.070
Y_0.5 0	Pr(>χ²) <0.0001	R²_4,194.6 0.135
max \|∂log L/∂β\| 3×10^-7	Score χ² 31.23	\|Pr(Y ≥ median)-½\| 0.294
	Pr(>χ²) <0.0001

	β	S.E.	Wald Z	Pr(>\|Z\|)
y≥1	-1.6268	0.4005	-4.06	<0.0001
y≥2	-2.9680	0.4325	-6.86	<0.0001
y≥3	-4.3895	0.5421	-8.10	<0.0001
y≥4	-5.6534	0.8068	-7.01	<0.0001
y≥6	-6.3476	1.0728	-5.92	<0.0001
r_sex=Male	-1.0657	0.2688	-3.96	<0.0001
r_age_group=≥ 60	-0.7161	0.3081	-2.32	0.0201
charlson	0.1234	0.0564	2.19	0.0286
assignment=Control	0.6978	0.2685	2.60	0.0094

label	levels	effect	conf.low	conf.high	d.f.	P
Treatment assignment	Case vs. Control	0.653	0.338	1.262	1	0.205
Charlson index	9 vs. 5	2.221	1.267	3.895	1	0.005
Sex	Female vs. Male	1.538	0.798	2.962	1	0.198
Age group	< 60 vs. >= 60	1.147	0.504	2.609	1	0.744

Logistic (Proportional Odds) Ordinal Regression Model

orm(formula = as.formula(paste0(VAR, covs)), data = DAT %>% mutate(outcome_trt_mod_binary = outcome_trt_mod_binary == 
    "Yes"))

	Model Likelihood Ratio Test	Discrimination Indexes	Rank Discrim. Indexes
Obs 387	LR χ² 12.38	R² 0.055	ρ 0.182
0 343	d.f. 4	R²_4,387 0.021
1 32	Pr(>χ²) 0.0147	R²_4,117.3 0.069
2 12	Score χ² 11.84	\|Pr(Y ≥ median)-½\| 0.386
Distinct Y 3	Pr(>χ²) 0.0186
Y_0.5 0
max \|∂log L/∂β\| 0.004

	β	S.E.	Wald Z	Pr(>\|Z\|)
y≥1	-3.4738	0.5686	-6.11	<0.0001
y≥2	-4.8887	0.6257	-7.81	<0.0001
r_sex=Male	-0.4303	0.3345	-1.29	0.1983
r_age_group=≥ 60	-0.1370	0.4194	-0.33	0.7439
charlson	0.1995	0.0716	2.78	0.0054
assignment=Control	0.4255	0.3357	1.27	0.2050

label	levels	effect	conf.low	conf.high	d.f.	P
Treatment assignment	Case vs. Control	1.016	0.511	2.016	1	0.965
Charlson index	9 vs. 5	1.923	1.057	3.500	1	0.032
Sex	Female vs. Male	2.221	1.102	4.474	1	0.026
Age group	< 60 vs. >= 60	0.893	0.368	2.168	1	0.802

Logistic (Proportional Odds) Ordinal Regression Model

orm(formula = as.formula(paste0(VAR, covs)), data = DAT %>% mutate(outcome_trt_mod_binary = outcome_trt_mod_binary == 
    "Yes"))

	Model Likelihood Ratio Test	Discrimination Indexes	Rank Discrim. Indexes
Obs 387	LR χ² 9.99	R² 0.054	ρ 0.165
FALSE 349	d.f. 4	R²_4,387 0.015
TRUE 38	Pr(>χ²) 0.0405	R²_4,102.8 0.057
Distinct Y 2	Score χ² 9.63	\|Pr(Y ≥ median)-½\| 0.402
Y_0.5 1	Pr(>χ²) 0.0471
max \|∂log L/∂β\| 0.003

	β	S.E.	Wald Z	Pr(>\|Z\|)
Intercept	-3.0998	0.5832	-5.32	<0.0001
r_sex=Male	-0.7978	0.3574	-2.23	0.0256
r_age_group=≥ 60	0.1133	0.4526	0.25	0.8023
charlson	0.1635	0.0764	2.14	0.0322
assignment=Control	-0.0154	0.3499	-0.04	0.9649

5.5.2 Combined summaries

Results¹	Healthcare utilization	Dose modification	Treatment modification
mITT
Questionnaire response Yes vs. No	0.5 (0.2-1) 0.064	0.7 (0.3-1.7) 0.488	0.6 (0.2-1.6) 0.325
Charlson index 9 vs. 5	1.6 (1.1-2.5) 0.028	2.2 (1.3-3.9) 0.005	1.9 (1-3.4) 0.043
Sex Female vs. Male	2.8 (1.7-4.7) <0.001	1.5 (0.8-2.9) 0.209	2.1 (1-4.3) 0.036
Age group < 60 vs. >= 60	2 (1.1-3.6) 0.026	1.1 (0.5-2.6) 0.766	0.9 (0.4-2.1) 0.765
Per protocol
Questionnaire response Yes vs. No	0.4 (0.2-0.9) 0.025	0.6 (0.3-1.5) 0.320	0.6 (0.2-1.8) 0.388
Charlson index 9 vs. 5	1.5 (0.9-2.5) 0.116	1.7 (0.9-3.2) 0.092	1.9 (0.9-3.9) 0.090
Sex Female vs. Male	3.4 (1.9-6.2) <0.001	1.6 (0.8-3.4) 0.188	1.5 (0.7-3.5) 0.325
Age group < 60 vs. >= 60	1.5 (0.8-3.1) 0.223	0.9 (0.3-2.2) 0.779	0.8 (0.2-2.3) 0.625
ITT
Treatment assignment Case vs. Control	0.5 (0.3-0.8) 0.009	0.7 (0.3-1.3) 0.205	1 (0.5-2) 0.965
Charlson index 9 vs. 5	1.6 (1.1-2.5) 0.029	2.2 (1.3-3.9) 0.005	1.9 (1.1-3.5) 0.032
Sex Female vs. Male	2.9 (1.7-4.9) <0.001	1.5 (0.8-3) 0.198	2.2 (1.1-4.5) 0.026
Age group < 60 vs. >= 60	2 (1.1-3.7) 0.020	1.1 (0.5-2.6) 0.744	0.9 (0.4-2.2) 0.802
¹Odds ratio (95% CI) p value